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Metabolism and immunity in breast cancer

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Abstract

Breast cancer is one of the most common malignancies that seriously threaten women’s health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host’s immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.

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References

  1. Li H, Zheng RS, Zhang SW, Zeng HM, Sun KX, Xia CF, Yang ZX, Chen WQ, He J. Incidence and mortality of female breast cancer in China, 2014. Chin J Oncol (Zhonghua Zhong LiuZaZhi) 2018; 40(3): 166–171 (in Chinese)

    CAS  Google Scholar 

  2. Stienstra R, Netea-Maier RT, Riksen NP, Joosten LAB, Netea MG. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Cell Metab 2017; 26(1): 142–156

    CAS  PubMed  Google Scholar 

  3. Kishton RJ, Sukumar M, Restifo NP. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab 2017; 26(1): 94–109

    CAS  PubMed  PubMed Central  Google Scholar 

  4. El Ansari R, McIntyre A, Craze ML, Ellis IO, Rakha EA, Green AR. Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations. Histopathology 2018; 72 (2): 183–190

    PubMed  Google Scholar 

  5. Cappelletti V, Iorio E, Miodini P, Silvestri M, Dugo M, Daidone MG. Metabolic footprints and molecular subtypes in breast cancer. Dis Markers 2017; 2017: 7687851

    PubMed  PubMed Central  Google Scholar 

  6. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418): 61–70

    Google Scholar 

  7. Holm K, Hegardt C, Staaf J, Vallon-Christersson J, Jönsson G, Olsson H, Borg A, Ringnér M. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res 2010; 12(3): R36

    PubMed  PubMed Central  Google Scholar 

  8. Yersal O, Barutca S. Biological subtypes of breast cancer: prognostic and therapeutic implications. World J Clin Oncol 2014; 5(3): 412–424

    PubMed  PubMed Central  Google Scholar 

  9. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200(3): 290–297

    CAS  PubMed  Google Scholar 

  10. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009; 101(10): 736–750

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, Kiezun A, Kryukov GV, Carter SL, Saksena G, Harris S, Shah RR, Resnick MA, Getz G, Gordenin DA. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013; 45(9): 970–976

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheng YC, Rondón G, Anderlini P, Khouri IF, Champlin RE, Ueno NT. Paclitaxel and trastuzumab as maintenance therapy in patients with HER2-positive metastatic breast cancer who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. J Cancer 2013; 4(8): 679–685

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Duru N, Candas D, Jiang G, Li JJ. Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 2014; 140(1): 1–14

    CAS  PubMed  Google Scholar 

  14. Malik F, Korkaya H, Clouthier SG, Wicha MS. Lin28 and HER2: two stem cell regulators conspire to drive aggressive breast cancer. Cell Cycle 2012; 11(15): 2780–2781

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 2013; 73(12): 3489–3493

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Russnes HG, Lingjærde OC, Børresen-Dale AL, Caldas C. Breast cancer molecular stratification: from intrinsic subtypes to integrative clusters. Am J Pathol 2017; 187(10): 2152–2162

    CAS  PubMed  Google Scholar 

  17. Prat A, Cruz C, Hoadley KA, Díez O, Perou CM, Balmaña J. Molecular features of the basal-like breast cancer subtype based on BRCA1 mutation status. Breast Cancer Res Treat 2014; 147(1): 185–191

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim SH, Choi SI, Won KY, Lim SJ. Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer. Pathol Res Pract 2016; 212(10): 904–910

    CAS  PubMed  Google Scholar 

  19. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science 2006; 312(5780): 1650–1653

    CAS  PubMed  Google Scholar 

  20. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126(1): 107–120

    CAS  PubMed  Google Scholar 

  21. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004; 64(11): 3892–3899

    CAS  PubMed  Google Scholar 

  22. Xu J, Chen Y, Olopade OI. MYC and breast cancer. Genes Cancer 2010; 1(6): 629–640

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008; 105(48): 18782–18787

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458(7239): 762–765

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lim SO, Li CW, Xia W, Lee HH, Chang SS, Shen J, Hsu JL, Raftery D, Djukovic D, Gu H, Chang WC, Wang HL, Chen ML, Huo L, Chen CH, Wu Y, Sahin A, Hanash SM, Hortobagyi GN, Hung MC. EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Res 2016; 76(5): 1284–1296

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kanaan YM, Sampey BP, Beyene D, Esnakula AK, Naab TJ, Ricks-Santi LJ, Dasi S, Day A, Blackman KW, Frederick W, Copeland RL Sr, Gabrielson E, Dewitty RL Jr. Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteomics 2014; 11(6): 279–294

    PubMed  Google Scholar 

  27. Kim S, Kim DH, Jung WH, Koo JS. Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer 2013; 20(3): 339–348

    CAS  PubMed  Google Scholar 

  28. Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjøsne H, Giskeødegård GF, Bathen TF. Metabolic characterization of triple negative breast cancer. BMC Cancer 2014; 14(1): 941

    PubMed  PubMed Central  Google Scholar 

  29. McGuirk S, Gravel SP, Deblois G, Papadopoli DJ, Faubert B, Wegner A, Hiller K, Avizonis D, Akavia UD, Jones RG, Giguère V, St-Pierre J. PGC-1α supports glutamine metabolism in breast cancer. Cancer Metab 2013; 1(1): 22

    PubMed  PubMed Central  Google Scholar 

  30. Monaco ME. Fatty acid metabolism in breast cancer subtypes. Oncotarget 2017; 8(17): 29487–29500

    PubMed  PubMed Central  Google Scholar 

  31. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6(1): 1–6

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, Eyob H, Kajimura S, Tward A, Krings G, Nomura DK, Goga A. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 2016; 22(4): 427–432

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23(1): 27–47

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Benjamin DI, Cravatt BF, Nomura DK. Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metab 2012; 16(5): 565–577

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Islam RA, Hossain S, Chowdhury EH. Potential therapeutic targets in energy metabolism pathways of breast cancer. Curr Cancer Drug Targets 2017; 17(8): 707–721

    CAS  PubMed  Google Scholar 

  36. Jin L, Zhou Y. Crucial role of the pentose phosphate pathway in malignant tumors. Oncol Lett 2019; 17(5): 4213–4221

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang Z, Dong C. Gluconeogenesis in cancer: function and regulation of PEPCK, FBPase, and G6Pase. Trends Cancer 2019; 5 (1): 30–45

    CAS  PubMed  Google Scholar 

  38. Brovkovych V, Aldrich A, Li N, Atilla-Gokcumen GE, Frasor J. Removal of serum lipids and lipid-derived metabolites to investigate breast cancer cell biology. Proteomics 2019; 19(18): e1800370

    PubMed  PubMed Central  Google Scholar 

  39. Gomes L, Sorgine M, Passos CLA, Ferreira C, de Andrade IR, Silva JL, Atella GC, Mermelstein CS, Fialho E. Increase in fatty acids and flotillins upon resveratrol treatment of human breast cancer cells. Sci Rep 2019; 9(1): 13960

    PubMed  PubMed Central  Google Scholar 

  40. Gago-Dominguez M, Jiang X, Castelao JE. Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res 2007; 9(1): 201

    PubMed  PubMed Central  Google Scholar 

  41. Chen Z, Wang Y, Warden C, Chen S. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol 2015; 149: 118–127

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Geck RC, Toker A. Nonessential amino acid metabolism in breast cancer. Adv Biol Regul 2016; 62: 11–17

    CAS  PubMed  Google Scholar 

  43. Wu Z, Wu J, Zhao Q, Fu S, Jin J. Emerging roles of aerobic glycolysis in breast cancer. Clin Transl Oncol 2020; 22(5): 631–646

    CAS  PubMed  Google Scholar 

  44. Macheda ML, Rogers S, Best JD. Molecularandcellularregulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005; 202(3): 654–662

    CAS  PubMed  Google Scholar 

  45. Deng Y, Zou J, Deng T, Liu J. Clinicopathological and prognostic significance of GLUT1 in breast cancer: a meta-analysis. Medicine (Baltimore) 2018; 97(48): e12961

    CAS  Google Scholar 

  46. Liu H, Ertay A, Peng P, Li J, Liu D, Xiong H, Zou Y, Qiu H, Hancock D, Yuan X, Huang WC, Ewing RM, Downward J, Wang Y. SGLT1 is required for the survival of triple-negative breast cancer cells via potentiation of EGFR activity. Mol Oncol 2019; 13 (9): 1874–1886

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lai B, Xiao Y, Pu H, Cao Q, Jing H, Liu X. Overexpression of SGLT1 is correlated with tumor development and poor prognosis of ovarian carcinoma. Arch Gynecol Obstet 2012; 285(5): 1455–1461

    CAS  PubMed  Google Scholar 

  48. Hanabata Y, Nakajima Y, Morita K, Kayamori K, Omura K. Coexpression of SGLT1 and EGFR is associated with tumor differentiation in oral squamous cell carcinoma. Odontology 2012; 100(2): 156–163

    CAS  PubMed  Google Scholar 

  49. Casneuf VF, Fonteyne P, Van Damme N, Demetter P, Pauwels P, de Hemptinne B, De Vos M, Van de Wiele C, Peeters M. Expression of SGLT1, Bcl-2 and p53 in primary pancreatic cancer related to survival. Cancer Invest 2008; 26(8): 852–859

    CAS  PubMed  Google Scholar 

  50. Brown RS, Goodman TM, Zasadny KR, Greenson JK, Wahl RL. Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nucl Med Biol 2002; 29(4): 443–453

    CAS  PubMed  Google Scholar 

  51. O’Neal J, Clem A, Reynolds L, Dougherty S, Imbert-Fernandez Y, Telang S, Chesney J, Clem BF. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer. Breast Cancer Res Treat 2016; 160(1): 29–40

    PubMed  Google Scholar 

  52. Lin Y, Lv F, Liu F, Guo X, Fan Y, Gu F, Gu J, Fu L. High expression of pyruvate kinase M2 is associated with chemosensitivity to epirubicin and 5-fluorouracil in breast cancer. J Cancer 2015; 6(11): 1130–1139

    PubMed  PubMed Central  Google Scholar 

  53. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey B, Hay N. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013; 24(2): 213–228

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mishra D, Banerjee D. Lactate dehydrogenases as metabolic links between tumor and stroma in the tumor microenvironment. Cancers (Basel) 2019; 11(6): E750

    Google Scholar 

  55. Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins 2001; 43(2): 175–185

    CAS  PubMed  Google Scholar 

  56. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci 2014; 39(8): 347–354

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Pu H, Zhang Q, Zhao C, Shi L, Wang Y, Wang J, Zhang M. Overexpression of G6PD is associated with high risks of recurrent metastasis and poor progression-free survival in primary breast carcinoma. World J Surg Oncol 2015; 13(1): 323

    PubMed  PubMed Central  Google Scholar 

  58. Yang X, Peng X, Huang J. Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation. Clin Transl Oncol 2018; 20(9): 1145–1152

    CAS  PubMed  Google Scholar 

  59. Chen JQ, Russo J. Dysregulation ofglucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 2012; 1826(2): 370–384

    CAS  PubMed  Google Scholar 

  60. Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014; 23(9): 2440–2446

    CAS  PubMed  Google Scholar 

  61. Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 2014; 99(10): E2046–E2050

    CAS  PubMed  Google Scholar 

  62. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE, Downing JR. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015; 373 (24): 2336–2346

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fieuw A, Kumps C, Schramm A, Pattyn F, Menten B, Antonacci F, Sudmant P, Schulte JH, Van Roy N, Vergult S, Buckley PG, De Paepe A, Noguera R, Versteeg R, Stallings R, Eggert A, Vandesompele J, De Preter K, Speleman F. Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas. Int J Cancer 2012; 130(11): 2599–2606

    CAS  PubMed  Google Scholar 

  64. Jiménez-Morales S, Pérez-Amado CJ, Langley E, Hidalgo-Miranda A. Overview of mitochondrial germline variants and mutations in human disease: focus on breast cancer. Int J Oncol 2018; 53(3): 923–936

    PubMed  Google Scholar 

  65. Montal ED, Dewi R, Bhalla K, Ou L, Hwang BJ, Ropell AE, Gordon C, Liu WJ, DeBerardinis RJ, Sudderth J, Twaddel W, Boros LG, Shroyer KR, Duraisamy S, Drapkin R, Powers RS, Rohde JM, Boxer MB, Wong KK, Girnun GD. PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Mol Cell 2015; 60(4): 571–583

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen J, Lee HJ, Wu X, Huo L, Kim SJ, Xu L, Wang Y, He J, Bollu LR, Gao G, Su F, Briggs J, Liu X, Melman T, Asara JM, Fidler IJ, Cantley LC, Locasale JW, Weihua Z. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. Cancer Res 2015; 75(3): 554–565

    CAS  PubMed  Google Scholar 

  67. Cao Y. Obesity protects cancer from drugs targeting blood vessels. Cell Metab 2018; 27(6): 1163–1165

    CAS  PubMed  Google Scholar 

  68. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029–1033

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Baumann J, Sevinsky C, Conklin DS. Lipid biology of breast cancer. Biochim Biophys Acta 2013; 1831(10): 1509–1517

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhao J, Zhi Z, Wang C, Xing H, Song G, Yu X, Zhu Y, Wang X, Zhang X, Di Y. Exogenous lipids promote the growth of breast cancer cells via CD36. Oncol Rep 2017; 38(4): 2105–2115

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, Cheng L, Masterson TA, Liu X, Ratliff TL, Cheng JX. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 2014; 19(3): 393–406

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cao Y. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest 2019; 129(8): 3006–3017

    PubMed  PubMed Central  Google Scholar 

  73. Jung YY, Kim HM, Koo JS. Expression of lipid metabolism-related proteins in metastatic breast cancer. PLoS One 2015; 10(9): e0137204

    PubMed  PubMed Central  Google Scholar 

  74. Iwamoto H, Abe M, Yang Y, Cui D, Seki T, Nakamura M, Hosaka K, Lim S, Wu J, He X, Sun X, Lu Y, Zhou Q, Shi W, Torimura T, Nie G, Li Q, Cao Y. Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metab 2018; 28(1): 104–117.e5

    CAS  PubMed  Google Scholar 

  75. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol 2017; 24(9): 1161–1180

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Min HY, Lee HY. Oncogene-driven metabolic alterations in cancer. Biomol Ther (Seoul) 2018; 26(1): 45–56

    CAS  Google Scholar 

  77. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012; 481(7381): 380–384

    CAS  Google Scholar 

  78. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104(49): 19345–19350

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Szutowicz A, Kwiatkowski J, Angielski S. Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br J Cancer 1979; 39(6): 681–687

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee JH, Jang H, Lee SM, Lee JE, Choi J, Kim TW, Cho EJ, Youn HD. ATP-citrate lyase regulates cellular senescence via an AMPK-and p53-dependent pathway. FEBS J 2015; 282(2): 361–371

    CAS  PubMed  Google Scholar 

  81. Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes offatty acid and cholesterol biosynthesis. FEBS Lett 1987; 223(2): 217–222

    CAS  PubMed  Google Scholar 

  82. Corominas-Faja B, Vellon L, Cuyàs E, Buxó M, Martin-Castillo B, Serra D, García J, Lupu R, Menendez JA. Clinical and therapeutic relevance of the metabolic oncogene fatty acid synthase in HER2+ breast cancer. Histol Histopathol 2017; 32(7): 687–698

    CAS  PubMed  Google Scholar 

  83. Singh R, Cuervo AM. Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol 2012; 2012: 282041

    PubMed  PubMed Central  Google Scholar 

  84. Yen MC, Kan JY, Hsieh CJ, Kuo PL, Hou MF, Hsu YL. Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance. Oncol Rep 2017; 37(6): 3253–3260

    CAS  PubMed  Google Scholar 

  85. Orlando UD, Castillo AF, Medrano MAR, Solano AR, Maloberti PM, Podesta EJ. Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem Pharmacol 2019; 159: 52–63

    CAS  PubMed  Google Scholar 

  86. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 1994; 91(14): 6379–6383

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Freedman LS, Clifford C, Messina M. Analysis of dietary fat, calories, body weight, and the development ofmammary tumors in rats and mice: a review. Cancer Res 1990; 50(18): 5710–5719

    CAS  PubMed  Google Scholar 

  88. Zimmerman AW, Veerkamp JH. New insights into the structure and function of fatty acid-binding proteins. Cell Mol Life Sci 2002; 59(7): 1096–1116

    CAS  PubMed  Google Scholar 

  89. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17(11): 1498–1503

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Li HY, Lv BB, Bi YH. FABP4 accelerates glioblastoma cell growth and metastasis through Wnt10b signalling. Eur Rev Med Pharmacol Sci 2018; 22(22): 7807–7818

    PubMed  Google Scholar 

  91. Guaita-Esteruelas S, Bosquet A, Saavedra P, Gumà J, Girona J, Lam EW, Amillano K, Borràs J, Masana L. Exogenous FABP4 increases breast cancer cell proliferation and activates the expression of fatty acid transport proteins. Mol Carcinog 2017; 56(1): 208–217

    CAS  PubMed  Google Scholar 

  92. Cheng F, Wang Z, Huang Y, Duan Y, Wang X. Investigation of salivary free amino acid profile for early diagnosis of breast cancer with ultra performance liquid chromatography-mass spectrometry. Clin Chim Acta 2015; 447: 23–31

    CAS  PubMed  Google Scholar 

  93. Erickson JW, Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget 2010; 1(8): 734–740

    PubMed  PubMed Central  Google Scholar 

  94. Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL, Eltayeb AE, Demas DM, Warri AM, Facey CO, Hilakivi-Clarke LA, Clarke R. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol Cancer 2014; 13(1): 239

    PubMed  PubMed Central  Google Scholar 

  95. Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T, Rabinowitz JD. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol 2013; 9(1): 712

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Cha YJ, Kim ES, Koo JS. Amino acid transporters and glutamine metabolism in breast cancer. Int J Mol Sci 2018; 19(3): E907

    PubMed  Google Scholar 

  97. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O’Toole SA, Rasko JE, Holst J. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 2016; 35(24): 3201–3208

    CAS  PubMed  Google Scholar 

  98. Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci 2012; 103(2): 382–389

    CAS  PubMed  Google Scholar 

  99. Pollari S, Käkönen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 2011; 125(2): 421–430

    CAS  PubMed  Google Scholar 

  100. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011; 476(7360): 346–350

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012; 336(6084): 1040–1044

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim SK, Jung WH, Koo JS. Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes. PLoS One 2014; 9(6): e101004

    PubMed  PubMed Central  Google Scholar 

  103. Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 2014; 7(4): 1248–1258

    CAS  PubMed  Google Scholar 

  104. Schito L, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2016; 2(12): 758–770

    PubMed  Google Scholar 

  105. Rey S, Schito L, Koritzinsky M, Wouters BG. Molecular targeting of hypoxia in radiotherapy. Adv Drug Deliv Rev 2017; 109: 45–62

    CAS  PubMed  Google Scholar 

  106. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97(6): 1573–1581

    PubMed  Google Scholar 

  107. Gruber G, Greiner RH, Hlushchuk R, Aebersold DM, Altermatt HJ, Berclaz G, Djonov V. Hypoxia-inducible factor 1 a in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 2004; 6(3): R191–R198

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Guo X, Lee S, Cao P. The inhibitive effect of sh-HIF1A-AS2 on the proliferation, invasion, and pathological damage of breast cancer via targeting miR-548c-3p through regulating HIF-1α/VEGF pathway in vitro and vivo. OncoTargets Ther2019; 12: 825–834

  109. Wang Y, Zhang G, Han J. HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer. J Cell Biochem 2019; 120(6): 10513–10518

    CAS  PubMed  Google Scholar 

  110. Zhang HS, Du GY, Zhang ZG, Zhou Z, Sun HL, Yu XY, Shi YT, Xiong DN, Li H, Huang YH. NRF2 facilitates breast cancer cell growth via HIF1-mediated metabolic reprogramming. Int J Biochem Cell Biol 2018; 95: 85–92

    CAS  PubMed  Google Scholar 

  111. Ponente M, Campanini L, Cuttano R, Piunti A, Delledonne GA, Coltella N, Valsecchi R, Villa A, Cavallaro U, Pattini L, Doglioni C, Bernardi R. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes. JCI Insight 2017; 2(4): e87380

    PubMed  PubMed Central  Google Scholar 

  112. Sethuraman A, Brown M, Seagroves TN, Wu ZH, Pfeffer LM, Fan M. SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. Breast Cancer Res 2016; 18 (1): 81

    PubMed  PubMed Central  Google Scholar 

  113. Deb S, Johansson I, Byrne D, Nilsson C, kConFab Investigators, Constable L, Fjällskog ML, Dobrovic A, Hedenfalk I, Fox SB. Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer. Mod Pathol 2014; 27(9): 1223–1230

    CAS  PubMed  Google Scholar 

  114. Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, Raman V, Zhen L, Mitzner WA, Sukumar S, Semenza GL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 2012; 31(14): 1757–1770

    CAS  PubMed  Google Scholar 

  115. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21(12): 3995–4004

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 2000; 97(19): 10430–10435

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia-related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117(12): 880–885

    CAS  PubMed  Google Scholar 

  118. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, Basso G, Leo G, Rosato A, Bicciato S, Cordenonsi M, Piccolo S. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 2012; 487(7407): 380–384

    CAS  PubMed  Google Scholar 

  119. Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: two decades of knowledge. Cancer Sci 2018; 109(3): 560–571

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 2015; 42(4): 841–851

    CAS  PubMed  Google Scholar 

  121. Stubbs M, Griffiths JR. The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Adv Enzyme Regul 2010; 50(1): 44–55

    PubMed  Google Scholar 

  122. Ebert BL, Firth JD, Ratcliffe PJ. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 1995; 270(49): 29083–29089

    CAS  PubMed  Google Scholar 

  123. Tang Y, Zhu J, Huang D, Hu X, Cai Y, Song X, Song Z, Hong C, Feng Z, Kang F. Mandibular osteotomy-induced hypoxia enhances osteoclast activation and acid secretion by increasing glycolysis. J Cell Physiol 2019; 234(7): 11165–11175

    CAS  PubMed  Google Scholar 

  124. Chiche J, Pommier S, Beneteau M, Mondragón L, Meynet O, Zunino B, Mouchotte A, Verhoeyen E, Guyot M, Pages G, Mounier N, Imbert V, Colosetti P, Goncalvès D, Marchetti S, Brière J, Carles M, Thieblemont C, Ricci JE. GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-κB-dependent induction of HIF-1α. Leukemia 2015; 29(5): 1163–1176

    CAS  PubMed  Google Scholar 

  125. Zhang T, Zhu X, Wu H, Jiang K, Zhao G, Shaukat A, Deng G, Qiu C. Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: combined administration of Polydatin and 2-Deoxy-d-glucose. J Cell Mol Med 2019; 23(5): 3711–3723

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Hamaguchi T, Iizuka N, Tsunedomi R, Hamamoto Y, Miyamoto T, Iida M, Tokuhisa Y, Sakamoto K, Takashima M, Tamesa T, Oka M. Glycolysis module activated by hypoxia-inducible factor 1alpha is related to the aggressive phenotype of hepatocellular carcinoma. Int J Oncol 2008; 33(4): 725–731

    CAS  PubMed  Google Scholar 

  127. Kraemer LD, Schulte PM. Prior PCB exposure suppresses hypoxia-induced up-regulation of glycolytic enzymes in Fundulus heteroclitus. Comp Biochem Physiol C Toxicol Pharmacol 2004; 139(1–3): 23–29

    CAS  PubMed  Google Scholar 

  128. Cui XG, Han ZT, He SH, Wu XD, Chen TR, Shao CH, Chen DL, Su N, Chen YM, Wang T, Wang J, Song DW, Yan WJ, Yang XH, Liu T, Wei HF, Xiao J. HIF1/2a mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget 2017; 8 (15): 24840–24852

    PubMed  PubMed Central  Google Scholar 

  129. Sun Y, He W, Luo M, Zhou Y, Chang G, Ren W, Wu K, Li X, Shen J, Zhao X, Hu Y. SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism. Tumour Biol 2015; 36(6): 4133–4141

    CAS  PubMed  Google Scholar 

  130. Li S, Oh YT, Yue P, Khuri FR, Sun SY. Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells. Oncogene 2016; 35(5): 642–650

    CAS  PubMed  Google Scholar 

  131. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8(3): 224–236

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W. Activation of a HIF1α-PPARγ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 2009; 9(6): 512–524

    CAS  PubMed  Google Scholar 

  133. Wang H, Airola MV, Reue K. How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862(10 Pt B): 1131–1145

    CAS  PubMed  Google Scholar 

  134. Mylonis I, Sembongi H, Befani C, Liakos P, Siniossoglou S, Simos G. Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci 2012; 125(Pt 14): 3485–3493

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Triantafyllou EA, Georgatsou E, Mylonis I, Simos G, Paraskeva E. Expression of AGPAT2, an enzyme involved in the glycerophospholipid/triacylglycerol biosynthesis pathway, is directly regulated by HIF-1 and promotes survival and etoposide resistance of cancer cells under hypoxia. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863(9): 1142–1152

    CAS  PubMed  Google Scholar 

  136. Kucejova B, Sunny N E, Nguyen A D, Hallac R, Fu X, Pena-Llopis S, Mason RP, Deberardinis RJ, Xie XJ, Debose-Boyd R, Kodibagkar VD, Burgess SC, Brugarolas J. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Oncogene 2011; 30(18): 2147–2160

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Huang D, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL, Gao P, Zhang H. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 2014; 8(6): 1930–1942

    CAS  PubMed  Google Scholar 

  138. Liu Y, Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W. HIF-1α and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1α-mediated fatty acid β-oxidation. Toxicol Lett 2014; 226(2): 117–123

    CAS  PubMed  Google Scholar 

  139. Mylonis I, Simos G, Paraskeva E. Hypoxia-inducible factors and the regulation of lipid metabolism. Cells 2019; 8(3): E214

    PubMed  Google Scholar 

  140. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 2001; 276(12): 9519–9525

    CAS  PubMed  Google Scholar 

  141. Liu Q, Möller U, Flügel D, Kietzmann T. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood 2004; 104(13): 3993–4001

    CAS  PubMed  Google Scholar 

  142. Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001; 276(46): 43407–43412

    CAS  PubMed  Google Scholar 

  143. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008; 8(9): 705–713

    CAS  PubMed  Google Scholar 

  144. Jeon YK, Yoo DR, Jang YH, Jang SY, Nam MJ. Sulforaphane induces apoptosis in human hepatic cancer cells through inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase4, mediated by hypoxia inducible factor-1-dependent pathway. Biochim Biophys Acta 2011; 1814(10): 1340–1348

    CAS  PubMed  Google Scholar 

  145. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J Biol Chem 2006; 281 (14): 9030–9037

    CAS  PubMed  Google Scholar 

  146. Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L, Llorente-Cortés V. Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2011; 31(6): 1411–1420

    CAS  PubMed  Google Scholar 

  147. Perman JC, Boström P, Lindbom M, Lidberg U, StÅhlman M, Hägg D, Lindskog H, Scharin Täng M, Omerovic E, Mattsson Hultén L, Jeppsson A, Petursson P, Herlitz J, Olivecrona G, Strickland DK, Ekroos K, Olofsson SO, Borén J. The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest 2011; 121 (7): 2625–2640

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 2008; 68(4): 1003–1011

    CAS  PubMed  Google Scholar 

  149. Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Höning S, Eckardt KU, Warnecke C. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J 2010; 24(11): 4443–4458

    CAS  PubMed  Google Scholar 

  150. Xiang L, Mou J, Shao B, Wei Y, Liang H, Takano N, Semenza GL, Xie G. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis 2019; 10(2): 40

    PubMed  PubMed Central  Google Scholar 

  151. Deming SL, Nass SJ, Dickson RB, Trock BJ. C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br J Cancer 2000; 83(12): 1688–1695

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Fallah Y, Brundage J, Allegakoen P, Shajahan-Haq AN. MYC-driven pathways in breast cancer subtypes. Biomolecules 2017; 7 (3): E53

    PubMed  Google Scholar 

  153. Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 1997; 94(13): 6658–6663

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhang Y, Zhang X, Wang X, Gan L, Yu G, Chen Y, Liu K, Li P, Pan J, Wang J, Qin S. Inhibition of LDH-A by lentivirus-mediated small interfering RNA suppresses intestinal-type gastric cancer tumorigenicity through the downregulation of Oct4. Cancer Lett 2012; 321(1): 45–54

    CAS  PubMed  Google Scholar 

  155. Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 2004; 24(13): 5923–5936

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation ofglucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 2000; 275 (29): 21797–21800

    CAS  PubMed  Google Scholar 

  157. Corn PG, Ricci MS, Scata KA, Arsham AM, Simon MC, Dicker DT, El-Deiry WS. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 2005; 4(11): 1285–1294

    CAS  PubMed  Google Scholar 

  158. Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007; 12(2): 108–113

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res 2007; 67(3): 854–855

    CAS  PubMed  Google Scholar 

  160. Dang CV. The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found Symp Proc 2007; (4): 35–53

  161. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3(3): 177–185

    PubMed  Google Scholar 

  162. Lukey MJ, Wilson KF, Cerione RA. Therapeutic strategies impacting cancer cell glutamine metabolism. Future Med Chem 2013; 5(14): 1685–1700

    CAS  PubMed  Google Scholar 

  163. Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ, Bellovin DI, Tran PT, Philbrick WM, Garcia-Ocana A, Casey SC, Li Y, Dang CV, Zare RN, Felsher DW. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci USA 2015; 112 (21): 6539–6544

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Xiao D, Ren P, Su H, Yue M, Xiu R, Hu Y, Liu H, Qing G. Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2. Oncotarget 2015; 6(38): 40655–40666

    PubMed  PubMed Central  Google Scholar 

  165. Deng SJ, Chen HY, Zeng Z, Deng S, Zhu S, Ye Z, He C, Liu ML, Huang K, Zhong JX, Xu FY, Li Q, Liu Y, Wang C, Zhao G. Nutrient stress-dysregulated antisense lncRNA GLS-AS impairs GLS-mediated metabolism and represses pancreatic cancer progression. Cancer Res 2019; 79(7): 1398–1412

    CAS  PubMed  Google Scholar 

  166. Craze ML, Cheung H, Jewa N, Coimbra NDM, Soria D, El-Ansari R, Aleskandarany MA, Wai Cheng K, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR. MYC regulation ofglutamine-proline regulatory axis is key in luminal B breast cancer. Br J Cancer 2018; 118(2): 258–265

    CAS  PubMed  Google Scholar 

  167. Qie S, Chu C, Li W, Wang C, Sang N. ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation. J Cell Biochem 2014; 115(3): 498–509

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Haikala HM, Marques E, Turunen M, Klefström J. Myc requires RhoA/SRF to reprogram glutamine metabolism. Small GTPases 2018; 9(3): 274–282

    CAS  PubMed  Google Scholar 

  169. Sabnis HS, Somasagara RR, Bunting KD. Targeting MYC dependence by metabolic inhibitors in cancer. Genes (Basel) 2017; 8(4): E114

    Google Scholar 

  170. Soga T. Cancer metabolism: key players in metabolic reprogramming. Cancer Sci 2013; 104(3): 275–281

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Liu R, Li Y, Tian L, Shi H, Wang J, Liang Y, Sun B, Wang S, Zhou M, Wu L, Nie J, Lin B, Tang S, Zhang Y, Wang G, Zhang C, Han J, Xu B, Liu L, Gong K, Zheng T. Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma. Cancer Lett 2019; 443: 34–46

    CAS  PubMed  Google Scholar 

  172. Ritorto MS, Rhode H, Vogel A, Borlak J. Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC. Biol Chem 2016; 397(11): 1147–1162

    CAS  PubMed  Google Scholar 

  173. Blevins MA, Towers CG, Patrick AN, Zhao R, Ford HL. The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 2015; 19(2): 213–225

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Hua L, Fan L, Aichun W, Yongjin Z, Qingqing C, Xiaojian W. Inhibition of Six1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells. Tumour Biol 2014; 35(3): 1925–1931

    PubMed  Google Scholar 

  175. Yu Y, Davicioni E, Triche TJ, Merlino G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 2006; 66(4): 1982–1989

    CAS  PubMed  Google Scholar 

  176. Jin H, Cui M, Kong J, Cui X, Lin Z, Wu Q, Liu S. Sineoculis homeobox homolog 1 protein is associated with breast cancer progression and survival outcome. Exp Mol Pathol 2014; 97(2): 247–252

    CAS  PubMed  Google Scholar 

  177. Zhang Y, Wang S, Liu Z, Yang L, Liu J, Xiu M. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med 2019; 23(7): 4523–4533

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Xie Y, Jin P, Sun X, Jiao T, Zhang Y, Li Y, Sun M. SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial-mesenchymal transition. Cell Biochem Funct 2018; 36(8): 413–419

    CAS  PubMed  Google Scholar 

  179. Nishimura T, Tamaoki M, Komatsuzaki R, Oue N, Taniguchi H, Komatsu M, Aoyagi K, Minashi K, Chiwaki F, Shinohara H, Tachimori Y, Yasui W, Muto M, Yoshida T, Sakai Y, Sasaki H. SIX1 maintains tumor basal cells via transforming growth factor-β pathway and associates with poor prognosis in esophageal cancer. Cancer Sci 2017; 108(2): 216–225

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Dumay A, Feugeas JP, Wittmer E, Lehmann-Che J, Bertheau P, Espié M, Plassa LF, Cottu P, Marty M, André F, Sotiriou C, Pusztai L, de Thé H. Distinct tumor protein p53 mutants in breast cancer subgroups. Int J Cancer 2013; 132(5): 1227–1231

    CAS  PubMed  Google Scholar 

  181. Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 2018; 167(2): 417–423

    CAS  PubMed  Google Scholar 

  182. Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 2004; 64(7): 2627–2633

    CAS  PubMed  Google Scholar 

  183. Watanabe M, Naraba H, Sakyo T, Kitagawa T. DNA damage-induced modulation of GLUT3 expression is mediated through p53-independent extracellular signal-regulated kinase signaling in HeLa cells. Mol Cancer Res 2010; 8(11): 1547–1557

    CAS  PubMed  Google Scholar 

  184. Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 2012; 72(2): 560–567

    CAS  PubMed  Google Scholar 

  185. Mikawa T, Maruyama T, Okamoto K, Nakagama H, Lleonart ME, Tsusaka T, Hori K, Murakami I, Izumi T, Takaori-Kondo A, Yokode M, Peters G, Beach D, Kondoh H. Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2. J Cell Biol 2014; 204(5): 729–745

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Boidot R, Végran F, Meulle A, Le Breton A, Dessy C, Sonveaux P, Lizard-Nacol S, Feron O. Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res 2012; 72(4): 939–948

    CAS  PubMed  Google Scholar 

  187. Wang YB, Xu O, Zhang RJ, Shan CG. Study on the relationship between MCT-1 and p53 in laryngeal squamous cell carcinoma. J Clin Otorhinolaryngol Head Neck Surgery (Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi) 2017; 31(11): 825–829 (in Chinese)

    CAS  Google Scholar 

  188. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 2011; 13(3): 310–316

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Geng J, Yuan X, Wei M, Wu J, Qin ZH. The diverse role of TIGAR in cellular homeostasis and cancer. Free Radic Res 2018; 52(11–12): 1240–1249

    CAS  PubMed  Google Scholar 

  190. Ko YH, Domingo-Vidal M, Roche M, Lin Z, Whitaker-Menezes D, Seifert E, Capparelli C, Tuluc M, Birbe RC, Tassone P, Curry JM, Navarro-Sabaté À, Manzano A, Bartrons R, Caro J, Martinez-Outschoorn U. TP53-inducible glycolysis and apoptosis regulator (TIGAR) metabolically reprograms carcinoma and stromal cells in breast cancer. J Biol Chem 2016; 291(51): 26291–26303

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Zhou JH, Zhang TT, Song DD, Xia YF, Qin ZH, Sheng R. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis. Sci Rep 2016; 6(1): 27096

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Won KY, Lim SJ, Kim GY, Kim YW, Han SA, Song JY, Lee DK. Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer. Hum Pathol 2012; 43(2): 221–228

    CAS  PubMed  Google Scholar 

  193. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2013; 493 (7433): 542–546

    CAS  PubMed  Google Scholar 

  194. Amelio I, Markert EK, Rufini A, Antonov AV, Sayan BS, Tucci P, Agostini M, Mineo TC, Levine AJ, Melino G. p73 regulates serine biosynthesis in cancer. Oncogene 2014; 33(42): 5039–5046

    CAS  PubMed  Google Scholar 

  195. Liu J, Zhang C, Feng Z. Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai) 2014; 46(3): 170–179

    CAS  Google Scholar 

  196. Parrales A, Iwakuma T. p53 as a regulator of lipid metabolism in cancer. Int J Mol Sci 2016; 17(12): E2074

    PubMed  Google Scholar 

  197. Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L. Cracking the estrogen receptor’s posttranslational code in breast tumors. Endocr Rev 2011; 32(5): 597–622

    CAS  PubMed  Google Scholar 

  198. Vasudevan D, Hickok JR, Bovee RC, Pham V, Mantell LL, Bahroos N, Kanabar P, Cao XJ, Maienschein-Cline M, Garcia BA, Thomas DD. Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications. Cancer Res 2015; 75(24): 5299–5308

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Matic S, Quaglino E, Arata L, Riccardo F, Pegoraro M, Vallino M, Cavallo F, Noris E. The rat ErbB2 tyrosine kinase receptor produced in plants is immunogenic in mice and confers protective immunity against ErbB2+ mammary cancer. Plant Biotechnol J 2016; 14(1): 153–159

    CAS  PubMed  Google Scholar 

  200. Ji Y, Yang C, Tang Z, Yang Y, Tian Y, Yao H, Zhu X, Zhang Z, Ji J, Zheng X. Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation. Nat Commun 2017; 8(1): 15308

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, Xu YH, Dong B, Xiong Y, Lei QY, Guan KL. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 2013; 23(4): 464–476

    CAS  PubMed  Google Scholar 

  202. Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011; 334(6060): 1278–1283

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science 1996; 274(5295): 2100–2103

    CAS  PubMed  Google Scholar 

  204. Floyd ZE, Stephens JM. Control of peroxisome proliferator-activated receptor g 2 stability and activity by SUMOylation. Obes Res 2004; 12(6): 921–928

    CAS  PubMed  Google Scholar 

  205. Watanabe M, Takahashi H, Saeki Y, Ozaki T, Itoh S, Suzuki M, Mizushima W, Tanaka K, Hatakeyama S. The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARg. eLife 2015; 4: e05615

    PubMed  PubMed Central  Google Scholar 

  206. Brunmeir R, Xu F. Functional regulation of PPARs through post-translational modifications. Int J Mol Sci 2018; 19(6): E1738

    PubMed  Google Scholar 

  207. Xiaoping Z, Fajun Y. Regulation of SREBP-mediated gene expression. Sheng Wu Wu Li Hsueh Bao 2012; 28(4): 287–294

    PubMed  PubMed Central  Google Scholar 

  208. Ascenção CFR, Nagampalli RSK, Islam Z, Pinheiro MP, Menezes Dos Reis L, Pauletti BA, de Guzzi Cassago CA, Granato DC, Paes Leme AF, Dias SMG. N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration. Biochimie 2018; 154: 69–76

    PubMed  Google Scholar 

  209. Han T, Zhan W, Gan M, Liu F, Yu B, Chin YE, Wang JB. Phosphorylation of glutaminase by PKCe is essential for its enzymatic activity and critically contributes to tumorigenesis. Cell Res 2018; 28(6): 655–669

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 2008; 15(3): 521–529

    CAS  PubMed  Google Scholar 

  211. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, Peters EC, Driggers EM, Hsieh-Wilson LC. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012; 337(6097): 975–980

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Bertrand L, Alessi DR, Deprez J, Deak M, Viaene E, Rider MH, Hue L. Heart 6-phosphofructo-2-kinase activation by insulin results from Ser-466 and Ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase B. J Biol Chem 1999; 274(43): 30927–30933

    CAS  PubMed  Google Scholar 

  213. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Aleckovic M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, Chen J. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun 2013; 4(1): 1790

    PubMed  Google Scholar 

  214. Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012; 287(6): 3850–3858

    CAS  PubMed  Google Scholar 

  215. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2009; 2(97): ra73

    PubMed  PubMed Central  Google Scholar 

  216. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 2012; 14(12): 1295–1304

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y, Wang G, Huang Y, Xiong Y, Guan KL, Lei QY. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011; 42(6): 719–730

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, Gu TL, Aguiar M, Lonning S, Chen H, Mohammadi M, Britton LM, Garcia BA, Aleckovic M, Kang Y, Kaluz S, Devi N, Van Meir EG, Hitosugi T, Seo JH, Lonial S, Gaddh M, Arellano M, Khoury HJ, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014; 53(4): 534–548

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Fan J, Hitosugi T, Chung TW, Xie J, Ge Q, Gu TL, Polakiewicz RD, Chen GZ, Boggon TJ, Lonial S, Khuri FR, Kang S, Chen J. Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD+ redox homeostasis in cancer cells. Mol Cell Biol 2011; 31(24): 4938–4950

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL, Chen GZ, Boggon TJ, Lonial S, Fu H, Khuri FR, Kang S, Chen J. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 2011; 44(6): 864–877

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Fan J, Kang HB, Shan C, Elf S, Lin R, Xie J, Gu TL, Aguiar M, Lonning S, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 2014; 289(38): 26533–26541

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007; 64(7–8): 830–849

    CAS  PubMed  Google Scholar 

  223. Yi G, He Z, Zhou X, Xian L, Yuan T, Jia X, Hong J, He L, Liu J. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol 2013; 43(5): 1503–1510

    CAS  PubMed  Google Scholar 

  224. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408(6810): 307–310

    CAS  PubMed  Google Scholar 

  225. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 2002; 111(5): 709–720

    CAS  PubMed  Google Scholar 

  226. Giandomenico V, Simonsson M, Grönroos E, Ericsson J. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol Cell Biol 2003; 23 (7): 2587–2599

    CAS  PubMed  PubMed Central  Google Scholar 

  227. McDonald CJ, Acheff E, Kennedy R, Taylor L, Curthoys NP. Effect of lysine to alanine mutations on the phosphate activation and BPTES inhibition of glutaminase. Neurochem Int 2015; 88: 10–14

    CAS  PubMed  Google Scholar 

  228. Engin A. Obesity-associated breast cancer: analysis of risk factors. Adv Exp Med Biol 2017; 960: 571–606

    CAS  PubMed  Google Scholar 

  229. Haluska P, Menefee M, Plimack ER, Rosenberg J, Northfelt D, LaVallee T, Shi L, Yu XQ, Burke P, Huang J, Viner J, McDevitt J, LoRusso P. Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. Clin Cancer Res 2014; 20(18): 4747–4757

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Liang J, Mills GB. AMPK: a contextual oncogene or tumor suppressor? Cancer Res 2013; 73(10): 2929–2935

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Cao W, Li J, Hao Q, Vadgama JV, Wu Y. AMP-activated protein kinase: a potential therapeutic target for triple-negative breast cancer. Breast Cancer Res 2019; 21(1): 29

    PubMed  PubMed Central  Google Scholar 

  232. Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets 2017; 21(11): 1001–1016

    CAS  PubMed  Google Scholar 

  233. Kageyama S, Ii H, Taniguchi K, Kubota S, Yoshida T, Isono T, Chano T, Yoshiya T, Ito K, Yoshiki T, Kawauchi A, Nakata S. Mechanisms of tumor growth inhibition by depletion of γ-glutamylcyclotransferase (GGCT): a novel molecular target for anticancer therapy. Int J Mol Sci 2018; 19(7): E2054

    PubMed  Google Scholar 

  234. Ii H, Yoshiya T, Nakata S, Taniguchi K, Hidaka K, Tsuda S, Mochizuki M, Nishiuchi Y, Tsuda Y, Ito K, Kageyama S, Yoshiki T. A novel prodrug of a γ-glutamylcyclotransferase inhibitor suppresses cancer cell proliferation in vitro and inhibits tumor growth in a xenograft mouse model of prostate cancer. Chem-MedChem 2018; 13(2): 155–163

    CAS  Google Scholar 

  235. Curtin NJ, Hughes AN. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2001; 2(5): 298–306

    CAS  PubMed  Google Scholar 

  236. Burnet FM. The concept ofimmunological surveillance. Prog Exp Tumor Res 1970; 13: 1–27

    CAS  PubMed  Google Scholar 

  237. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 2014; 27: 16–25

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331(6024): 1565–1570

    CAS  PubMed  Google Scholar 

  239. Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol 2013; 34(11): 556–563

    CAS  PubMed  Google Scholar 

  240. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450–461

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Menzies AM, Long GV. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. Eur J Cancer 2013; 49(15): 3229–3241

    CAS  PubMed  Google Scholar 

  242. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192(2): 303–310

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J. Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol Immunother 2015; 64(7): 853–860

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Ward FJ, Dahal LN, Wijesekera SK, Abdul-Jawad SK, Kaewarpai T, Xu H, Vickers MA, Barker RN. The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur J Immunol 2013; 43(5): 1274–1285

    CAS  PubMed  Google Scholar 

  245. Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, Minghelli S, Morabito A, Fontana V, Pietra G, Carrega P, Ferrari N, Tosetti F, Chang LJ, Mingari MC, Ferlazzo G, Poggi A, Pistillo MP. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-α production. J Transl Med 2013; 11(1): 108

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Vonderheide RH, LoRusso PM, Khalil M, Gartner EM, Khaira D, Soulieres D, Dorazio P, Trosko JA, Rüter J, Mariani GL, Usari T, Domchek SM. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res 2010; 16(13): 3485–3494

    CAS  PubMed  Google Scholar 

  247. McArthur HL, Diab A, Page DB, Yuan J, Solomon SB, Sacchini V, Comstock C, Durack JC, Maybody M, Sung J, Ginsberg A, Wong P, Barlas A, Dong Z, Zhao C, Blum B, Patil S, Neville D, Comen EA, Morris EA, Kotin A, Brogi E, Wen YH, Morrow M, Lacouture ME, Sharma P, Allison JP, Hudis CA, Wolchok JD, Norton L. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin Cancer Res 2016; 22(23): 5729–5737

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224(1): 166–182

    CAS  PubMed  Google Scholar 

  249. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27(1): 111–122

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027–1034

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24(2): 207–212

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012; 366(26): 2517–2519

    CAS  PubMed  Google Scholar 

  253. Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 2015; 6(7): 5449–5464

    PubMed  Google Scholar 

  254. Chang LC, Chen TP, Kuo WK, Hua CC. The protein expression of PDL1 is highly correlated with those of eIF2a and ATF4 in lung cancer. Dis Markers 2018; 2018: 5068701

    PubMed  PubMed Central  Google Scholar 

  255. Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 2016; 27(3): 409–416

    CAS  PubMed  Google Scholar 

  256. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8(3): 239–245

    CAS  PubMed  Google Scholar 

  257. Shi T, Ma Y, Yu L, Jiang J, Shen S, Hou Y, Wang T. Cancer immunotherapy: a focus on the regulation ofimmune checkpoints. Int J Mol Sci 2018; 19(5): E1389

    PubMed  Google Scholar 

  258. Bedognetti D, Hendrickx W, Marincola FM, Miller LD. Prognostic and predictive immune gene signatures in breast cancer. Curr Opin Oncol 2015; 27(6): 433–444

    CAS  PubMed  Google Scholar 

  259. Bedognetti D, Maccalli C, Bader SB, Marincola FM, Seliger B. Checkpoint inhibitors and their application in breast cancer. Breast Care (Basel) 2016; 11(2): 108–115

    Google Scholar 

  260. Planes-Laine G, Rochigneux P, Bertucci F, Chrétien AS, Viens P, Sabatier R, Gonçalves A. PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging. a literature review. Cancers (Basel) 2019; 11(7): E1033

    Google Scholar 

  261. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23–34

    PubMed  PubMed Central  Google Scholar 

  262. Blackley EF, Loi S. Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast 2019; 48(Suppl 1): S44–S48

    PubMed  Google Scholar 

  263. DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 2007; 9(4): 212

    PubMed  PubMed Central  Google Scholar 

  264. Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA 2012; 109(8): 2796–2801

    CAS  PubMed  Google Scholar 

  265. Chin Y, Janseens J, Vandepitte J, Vandenbrande J, Opdebeek L, Raus J. Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer. Anticancer Res 1992; 12(5): 1463–1466

    CAS  PubMed  Google Scholar 

  266. Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer 2016; 4(1): 59

    PubMed  PubMed Central  Google Scholar 

  267. Kurozumi S, Inoue K, Matsumoto H, Fujii T, Horiguchi J, Oyama T, Kurosumi M, Shirabe K. Prognostic utility of tumor-infiltrating lymphocytes in residual tumor after neoadjuvant chemotherapy with trastuzumab for HER2-positive breast cancer. Sci Rep 2019; 9 (1): 1583

    PubMed  PubMed Central  Google Scholar 

  268. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, Syrjänen K. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 1992; 28(4–5): 859–864

    Google Scholar 

  269. Vikas P, Borcherding N, Zhang W. The clinical promise of immunotherapy in triple-negative breast cancer. Cancer Manag Res 2018; 10: 6823–6833

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012; 11(3): 215–233

    CAS  PubMed  Google Scholar 

  271. Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol 2016; 2(10): 1354–1360

    PubMed  Google Scholar 

  272. Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, Goubar A. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol 2015; 26(8): 1698–1704

    CAS  PubMed  PubMed Central  Google Scholar 

  273. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014; 32(27): 2959–2966

    PubMed  PubMed Central  Google Scholar 

  274. Zhang L, Wang XI, Ding J, Sun Q, Zhang S. The predictive and prognostic value of Foxp3+/CD25+ regulatory T cells and PD-L1 expression in triple negative breast cancer. Ann Diagn Pathol 2019; 40: 143–151

    PubMed  Google Scholar 

  275. Luen SJ, Salgado R, Dieci MV, Vingiani A, Curigliano G, Gould RE, Castaneda C, D’Alfonso T, Sanchez J, Cheng E, Andreopoulou E, Castillo M, Adams S, Demaria S, Symmans WF, Michiels S, Loi S. Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy. Ann Oncol 2019; 30(2): 236–242

    CAS  PubMed  Google Scholar 

  276. Criscitiello C. Tumor-associated antigens in breast cancer. Breast Care (Basel) 2012; 7(4): 262–266

    Google Scholar 

  277. Huber CH, Wölfel T. Immunotherapy of cancer: from vision to standard clinical practice. J Cancer Res Clin Oncol 2004; 130(7): 367–374

    CAS  PubMed  Google Scholar 

  278. Dols A, Smith JW 2nd, Meijer SL, Fox BA, Hu HM, Walker E, Rosenheim S, Moudgil T, Doran T, Wood W, Seligman M, Alvord WG, Schoof D, Urba WJ. Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 2003; 14(11): 1117–1123

    CAS  PubMed  Google Scholar 

  279. Cibotti R, Kanellopoulos JM, Cabaniols JP, Halle-Panenko O, Kosmatopoulos K, Sercarz E, Kourilsky P. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci USA 1992; 89(1): 416–420

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Shumway NM, Ibrahim N, Ponniah S, Peoples GE, Murray JL. Therapeutic breast cancer vaccines: a new strategy for early-stage disease. BioDrugs 2009; 23(5): 277–287

    CAS  PubMed  Google Scholar 

  281. Park JW, Melisko ME, Esserman LJ, Jones LA, Wollan JB, Sims R. Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 over-expressing breast cancer. J Clin Oncol 2007; 25(24): 3680–3687

    CAS  PubMed  Google Scholar 

  282. Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005; 5(4): 296–306

    CAS  PubMed  Google Scholar 

  283. Ladjemi MZ, Jacot W, Chardès T, Pèlegrin A, Navarro-Teulon I. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother 2010; 59(9): 1295–1312

    CAS  PubMed  PubMed Central  Google Scholar 

  284. Cannon MJ, Block MS, Morehead LC, Knutson KL. The evolving clinical landscape for dendritic cell vaccines and cancer immunotherapy. Immunotherapy 2019; 11(2): 75–79

    CAS  PubMed  Google Scholar 

  285. Saxena M, Balan S, Roudko V, Bhardwaj N. Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng 2018; 2 (6): 341–346

    PubMed  PubMed Central  Google Scholar 

  286. Eagles ME, Nassiri F, Badhiwala JH, Suppiah S, Almenawer SA, Zadeh G, Aldape KD. Dendritic cell vaccines for high-grade gliomas. Ther Clin Risk Manag 2018; 14: 1299–1313

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Sakai Y, Morrison BJ, Burke JD, Park JM, Terabe M, Janik JE, Forni G, Berzofsky JA, Morris JC. Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice. Cancer Res 2004; 64(21): 8022–8028

    CAS  PubMed  Google Scholar 

  288. Peoples GE, Goedegebuure PS, Smith R, Linehan DC, Yoshino I, Eberlein TJ. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 1995; 92(2): 432–436

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Al-Awadhi A, Lee Murray J, Ibrahim NK. Developing anti-HER2 vaccines: breast cancer experience. Int J Cancer 2018; 143(9): 2126–2132

    CAS  PubMed  Google Scholar 

  290. Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E, Pedicano JE, Gehan E, Peck RA, Arlen P, Tsang KY, Schlom J. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anticarcinoembryonic antigen immune responses. J Clin Oncol 2000; 18(23): 3964–3973

    CAS  PubMed  Google Scholar 

  291. Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Seipp CA, Einhorn JH, Roberts B, White DE. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J Natl Cancer Inst 1998; 90(24): 1894–1900

    CAS  PubMed  Google Scholar 

  292. Yang B, Jeang J, Yang A, Wu TC, Hung CF. DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother 2014; 10(11): 3153–3164

    PubMed  Google Scholar 

  293. Norell H, Poschke I, Charo J, Wei WZ, Erskine C, Piechocki MP, Knutson KL, Bergh J, Lidbrink E, Kiessling R. Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med 2010; 8(1): 53

    PubMed  PubMed Central  Google Scholar 

  294. Chae YC, Kim JH. Cancer stem cell metabolism: target for cancer therapy. BMB Rep 2018; 51(7): 319–326

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Louhichi T, Ziadi S, Saad H, Dhiab MB, Mestiri S, Trimeche M. Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer. Breast Cancer 2018; 25 (6): 698–705

    PubMed  Google Scholar 

  296. Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, Sugihara E, Onishi N, Yamamoto T, Yanagawa H, Suematsu M, Saya H. Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res 2012; 72(6): 1438–1448

    CAS  PubMed  Google Scholar 

  297. Liu PP, Liao J, Tang ZJ, Wu WJ, Yang J, Zeng ZL, Hu Y, Wang P, Ju HQ, Xu RH, Huang P. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ 2014; 21(1): 124–135

    PubMed  Google Scholar 

  298. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014; 514(7524): 628–632

    CAS  PubMed  PubMed Central  Google Scholar 

  299. Gao C, Shen Y, Jin F, Miao Y, Qiu X. Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS One 2016; 11(5): e0154576

    PubMed  PubMed Central  Google Scholar 

  300. Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sanchez V, Sanders ME, Lee T, Gomez H, Lluch A, Perez-Fidalgo J A, Wolf MM, Andrejeva G, Rathmell J C, Fesik S W, Arteaga CL. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 2017; 26(4): 633–647.e7

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Tirinato L, Liberale C, Di Franco S, Candeloro P, Benfante A, La Rocca R, Potze L, Marotta R, Ruffilli R, Rajamanickam VP, Malerba M, De Angelis F, Falqui A, Carbone E, Todaro M, Medema JP, Stassi G, Di Fabrizio E. Lipid droplets: a new player in colorectal cancer stem cells unveiled by spectroscopic imaging. Stem Cells 2015; 33(1): 35–44

    CAS  PubMed  Google Scholar 

  302. Wang T, Fahrmann J F, Lee H, Li Y J, Tripathi S C, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, Somlo G, Jandial R, Ann D, Hanash S, Jove R, Yu H. JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 2018; 27(1): 136–150.e5

    CAS  PubMed  Google Scholar 

  303. Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-oncol 2010; 12(11): 1113–1125

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73(3): 1128–1141

    CAS  PubMed  Google Scholar 

  305. Bottino C, Castriconi R, Moretta L, Moretta A. Cellular ligands of activating NK receptors. Trends Immunol 2005; 26(4): 221–226

    CAS  PubMed  Google Scholar 

  306. Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, Mortini P, Ferrone S, Doglioni C, Marincola FM, Galli R, Parmiani G, Maccalli C. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res 2010; 16(3): 800–813

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Silver DJ, Sinyuk M, Vogelbaum MA, Ahluwalia MS, Lathia JD. The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities. Neuro-oncol 2016; 18(2): 153–159

    PubMed  Google Scholar 

  308. Almozyan S, Colak D, Mansour F, Alaiya A, Al-Harazi O, Qattan A, Al-Mohanna F, Al-Alwan M, Ghebeh H. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer 2017; 141 (7): 1402–1412

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Biswas SK. Metabolic reprogramming of immune cells in cancer progression. Immunity 2015; 43(3): 435–449

    CAS  PubMed  Google Scholar 

  310. Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2015; 34(1): 82–100

    PubMed  Google Scholar 

  311. Ho PC, Liu PS. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. J Immunother Cancer 2016; 4(1): 4

    PubMed  PubMed Central  Google Scholar 

  312. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 2013; 24(6): 695–709

    CAS  PubMed  Google Scholar 

  313. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 2003; 163(4): 1233–1243

    CAS  PubMed  PubMed Central  Google Scholar 

  314. Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003; 112(5): 645–657

    CAS  PubMed  PubMed Central  Google Scholar 

  315. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513(7519): 559–563

    CAS  PubMed  PubMed Central  Google Scholar 

  316. Cassim S, Pouyssegur J. Tumor microenvironment: a metabolic player that shapes the immune response. Int J Mol Sci 2019; 21(1): E157

    PubMed  Google Scholar 

  317. Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai S W, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 2019; 178(1): 176–189.e15

    CAS  PubMed  PubMed Central  Google Scholar 

  318. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153(6): 1239–1251

    CAS  PubMed  PubMed Central  Google Scholar 

  319. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G, Yurchenko E, Raissi TC, van der Windt GJ, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015; 42(1): 41–54

    CAS  PubMed  Google Scholar 

  320. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186(6): 3299–3303

    CAS  PubMed  Google Scholar 

  321. Siska PJ, Rathmell JC. T cell metabolic fitness in antitumor immunity. Trends Immunol 2015; 36(4): 257–264

    CAS  PubMed  PubMed Central  Google Scholar 

  322. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014; 211(5): 781–790

    CAS  PubMed  PubMed Central  Google Scholar 

  323. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16(6): 769–777

    CAS  PubMed  Google Scholar 

  324. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6(1): 6692

    CAS  PubMed  Google Scholar 

  325. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162(6): 1229–1241

    CAS  PubMed  PubMed Central  Google Scholar 

  326. Saleh R, Taha RZ, Sasidharan Nair V, Alajez NM, Elkord E. PD-L1 blockade by atezolizumab downregulates signaling pathways associated with tumor growth, metastasis, and hypoxia in human triple negative breast cancer. Cancers (Basel) 2019; 11(8): E1050

    Google Scholar 

  327. Lim S, Liu H, Madeira da Silva L, Arora R, Liu Z, Phillips JB, Schmitt DC, Vu T, McClellan S, Lin Y, Lin W, Piazza GA, Fodstad O, Tan M. Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1α. Cancer Res 2016; 76(8): 2231–2242

    CAS  PubMed  PubMed Central  Google Scholar 

  328. Franchina DG, He F, Brenner D. Survival of the fittest: cancer challenges T cell metabolism. Cancer Lett 2018; 412: 216–223

    CAS  PubMed  Google Scholar 

  329. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 2009; 8(1): 88–96

    CAS  PubMed  Google Scholar 

  330. Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010; 123(1): 271–279

    CAS  PubMed  Google Scholar 

  331. Zhou X, Chen J, Yi G, Deng M, Liu H, Liang M, Shi B, Fu X, Chen Y, Chen L, He Z, Wang J, Liu J. Metformin suppresses hypoxia-induced stabilization of HIF-1 a through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 2016; 7(1): 873–884

    PubMed  Google Scholar 

  332. Xue J, Li L, Li N, Li F, Qin X, Li T, Liu M. Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1. Eur J Pharmacol 2019; 859: 172541

    CAS  PubMed  Google Scholar 

  333. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, Li CW, Kim T, Chang SS, Lee HH, Hsu JL, Wang HL, Kuo CW, Chang WC, Hadad S, Purdie CA, McCoy AM, Cai S, Tu Y, Litton JK, Mittendorf EA, Moulder SL, Symmans WF, Thompson AM, Piwnica-Worms H, Chen CH, Khoo KH, Hung MC. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell 2018; 71(4): 606–620.e7

    CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China

    Deyu Zhang, Xiaojie Xu & Qinong Ye

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  1. Deyu Zhang
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Deyu Zhang, Xiaojie Xu, and Qinong Ye declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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Zhang, D., Xu, X. & Ye, Q. Metabolism and immunity in breast cancer. Front. Med. 15, 178–207 (2021). https://doi.org/10.1007/s11684-020-0793-6

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