Skip to main content
SpringerLink
Log in

The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Breast cancer is the most common malignant tumor globally as of 2020 and remains the second leading cause of cancer-related death among female individuals worldwide. Metabolic reprogramming is well recognized as a hallmark of malignancy owing to the rewiring of multiple biological processes, notably, glycolysis, oxidative phosphorylation, pentose phosphate pathway, as well as lipid metabolism, which support the demands for the relentless growth of tumor cells and allows distant metastasis of cancer cells. Breast cancer cells are well documented to reprogram their metabolism via mutations or inactivation of intrinsic factors such as c-Myc, TP53, hypoxia-inducible factor, and the PI3K/AKT/mTOR pathway or crosstalk with the surrounding tumor microenvironments, including hypoxia, extracellular acidification and interaction with immune cells, cancer-associated fibroblasts, and adipocytes. Furthermore, altered metabolism contributes to acquired or inherent therapeutic resistance. Therefore, there is an urgent need to understand the metabolic plasticity underlying breast cancer progression as well as to dictate metabolic reprogramming that accounts for the resistance to standard of care. This review aims to illustrate the altered metabolism in breast cancer and its underlying mechanisms, as well as metabolic interventions in breast cancer treatment, with the intention to provide strategies for developing novel therapeutic treatments for breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Feng Y, et al. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 2018;5(2):77–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–19.

    Article  PubMed  Google Scholar 

  3. Siegel RL, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.

    Article  PubMed  Google Scholar 

  4. Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168(4):657–69.

    Article  CAS  PubMed  Google Scholar 

  5. Koboldt DC, et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

  6. Gao JJ, Swain SM. Luminal A breast cancer and molecular assays: a review. Oncologist. 2018;23(5):556–65.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ades F, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794–803.

    Article  PubMed  Google Scholar 

  8. Mery B, et al. Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé: New therapeutic strategies in HER2-positive breast cancer. Bull Cancer. 2021;108(11s):11s8–18.

  9. Schneeweiss A, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–84.

    Article  CAS  PubMed  Google Scholar 

  10. Choi BB, Jang HJ, Choi SI. Basal-like breast cancer: comparison of imaging characteristics. Curr Med Imaging. 2020;16(3):241–8.

    Article  PubMed  Google Scholar 

  11. Won KA, Spruck C. Triple-negative breast cancer therapy: current and future perspectives (review). Int J Oncol. 2020;57(6):1245–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cappelletti V, et al. Metabolic footprints and molecular subtypes in breast cancer. Dis Markers. 2017;2017:7687851.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Judge A, Dodd MS. Metabolism. Essays Biochem. 2020;64(4):607–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vaupel P, Schmidberger H, Mayer A. The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol. 2019;95(7):912–9.

    Article  CAS  PubMed  Google Scholar 

  15. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39(8):347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Anderson NM, et al. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9(2):216–37.

    Article  CAS  PubMed  Google Scholar 

  17. Bernard K, et al. Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation. J Biol Chem. 2018;293(4):1218–28.

    Article  CAS  PubMed  Google Scholar 

  18. Amores-Sánchez MI, Medina MA. Glutamine, as a precursor of glutathione, and oxidative stress. Mol Genet Metab. 1999;67(2):100–5.

    Article  PubMed  Google Scholar 

  19. Yang C, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56(3):414–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cory JG, Cory AH. Critical roles of glutamine as nitrogen donors in purine and pyrimidine nucleotide synthesis: asparaginase treatment in childhood acute lymphoblastic leukemia. In Vivo. 2006;20(5):587–9.

    CAS  PubMed  Google Scholar 

  21. Wang ZY, et al. LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis. Breast Cancer Res Treat. 2012;131(3):791–800.

    Article  CAS  PubMed  Google Scholar 

  22. Wang S, et al. Lactate dehydrogenase-A (LDH-A) preserves cancer stemness and recruitment of tumor-associated macrophages to promote breast cancer progression. Front Oncol. 2021;11: 654452.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wu Z, et al. Emerging roles of aerobic glycolysis in breast cancer. Clin Transl Oncol. 2020;22(5):631–46.

    Article  CAS  PubMed  Google Scholar 

  24. Shin E, Koo JS. Glucose metabolism and glucose transporters in breast cancer. Front Cell Dev Biol. 2021;9: 728759.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wellberg EA, et al. The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis. Breast Cancer Res. 2016;18(1):131.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202(3):654–62.

    Article  CAS  PubMed  Google Scholar 

  27. Burgman P, et al. Hypoxia-induced increase in FDG uptake in MCF7 cells. J Nucl Med. 2001;42(1):170–5.

    CAS  PubMed  Google Scholar 

  28. Hussein YR, et al. Glut-1 expression correlates with basal-like breast cancer. Transl Oncol. 2011;4(6):321–7.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Krzeslak A, et al. Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers. Pathol Oncol Res. 2012;18(3):721–8.

    Article  CAS  PubMed  Google Scholar 

  30. Chen Q, et al. Blockade of GLUT1 by WZB117 resensitizes breast cancer cells to adriamycin. Anticancer Drugs. 2017;28(8):880–7.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang T, et al. 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):3711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Farabegoli F, et al. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur J Pharm Sci. 2012;47(4):729–38.

    Article  CAS  PubMed  Google Scholar 

  33. El-Sisi A, et al. Oxamate potentiates taxol chemotherapeutic efficacy in experimentally-induced solid ehrlich carcinoma (SEC) in mice. Biomed Pharmacother. 2017;95:1565–73.

    Article  CAS  PubMed  Google Scholar 

  34. Ge T, et al. The role of the pentose phosphate pathway in diabetes and cancer. Front Endocrinol (Lausanne). 2020;11:365.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mele L, et al. Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation. J Exp Clin Cancer Res. 2019;38(1):160.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Huang C, et al. Interference with redox homeostasis through a G6PD-targeting self-assembled hydrogel for the enhancement of sonodynamic therapy in breast cancer. Front Chem. 2022;10: 908892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cremon C, et al. Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome. Aliment Pharmacol Ther. 2017;45(7):909–22.

    Article  CAS  PubMed  Google Scholar 

  38. Li Y, et al. Targeting glucose-6-phosphate dehydrogenase by 6-AN induces ROS-mediated autophagic cell death in breast cancer. FEBS J. 2022.

  39. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Marini JC, et al. Glutamine: precursor or nitrogen donor for citrulline synthesis? Am J Physiol Endocrinol Metab. 2010;299(1):E69-79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Saito Y, Soga T. Amino acid transporters as emerging therapeutic targets in cancer. Cancer Sci. 2021;112(8):2958–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li Y, et al. SLC7A5 serves as a prognostic factor of breast cancer and promotes cell proliferation through activating AKT/mTORC1 signaling pathway. Ann Transl Med. 2021;9(10):892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ryu HJ, Koo JS. Glucose and glutamine metabolism-related protein expression in breast ductal carcinoma in situ. Neoplasma. 2022;69(3):630–9.

    Article  PubMed  Google Scholar 

  44. El Ansari R, et al. The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours. Breast Cancer Res. 2018;20(1):21.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lampa M, et al. Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition. PLoS ONE. 2017;12(9): e0185092.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gross MI, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890–901.

    Article  CAS  PubMed  Google Scholar 

  47. DeMichele A, et al. Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS) in combination with paclitaxel (Pac) in patients (pts) with triple negative breast cancer (TNBC). J Clin Oncol. 2016;34(15_Suppl.):1011–111.

    Article  Google Scholar 

  48. Lukey MJ, et al. Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer. Cell Rep. 2019;29(1):76-88.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pan S, et al. Serine, glycine and one-carbon metabolism in cancer (review). Int J Oncol. 2021;58(2):158–70.

    Article  CAS  PubMed  Google Scholar 

  50. Possemato R, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476(7360):346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Samanta D, et al. PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Res. 2016;76(15):4430–42.

    Article  CAS  PubMed  Google Scholar 

  52. Gao S, et al. PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3β/β-catenin/cyclin D1 signaling pathway in ER-negative breast cancer. J Exp Clin Cancer Res. 2017;36(1):179.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Choi BH, et al. Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors. Cell Rep. 2022;38(3): 110278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Newman AC, Maddocks ODK. One-carbon metabolism in cancer. Br J Cancer. 2017;116(12):1499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Krebs MO, et al. One-carbon metabolism and schizophrenia: current challenges and future directions. Trends Mol Med. 2009;15(12):562–70.

    Article  CAS  PubMed  Google Scholar 

  56. Mentch SJ, Locasale JW. One-carbon metabolism and epigenetics: understanding the specificity. Ann N Y Acad Sci. 2016;1363(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  57. Zhu Z, Leung GKK. More than a metabolic enzyme: MTHFD2 as a novel target for anticancer therapy? Front Oncol. 2020;10:658.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lehtinen L, et al. High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion. Oncotarget. 2013;4(1):48–63.

    Article  PubMed  Google Scholar 

  59. Koufaris C, et al. Suppression of MTHFD2 in MCF-7 breast cancer cells increases glycolysis, dependency on exogenous glycine, and sensitivity to folate Ddpletion. J Proteome Res. 2016;15(8):2618–25.

    Article  CAS  PubMed  Google Scholar 

  60. Liu F, et al. Increased MTHFD2 expression is associated with poor prognosis in breast cancer. Tumour Biol. 2014;35(9):8685–90.

    Article  CAS  PubMed  Google Scholar 

  61. Mullarky E, et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc Natl Acad Sci USA. 2016;113(7):1778–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pacold ME, et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016;12(6):452–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eniafe J, Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene. 2021;40(19):3351–63.

    Article  CAS  PubMed  Google Scholar 

  64. Calderón-González KG, et al. Determination of the protein expression profiles of breast cancer cell lines by quantitative proteomics using iTRAQ labelling and tandem mass spectrometry. J Proteom. 2015;124:50–78.

    Article  Google Scholar 

  65. Gentric G, Mieulet V, Mechta-Grigoriou F. Heterogeneity in cancer metabolism: new concepts in an old field. Antioxid Redox Signal. 2017;26(9):462–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu WS, et al. Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability. Breast Cancer Res. 2018;20(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Han M, et al. Epigenetic enzyme mutations: role in tumorigenesis and molecular inhibitors. Front Oncol. 2019;9:194.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Chiang S, et al. IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity. Cancer Res. 2016;76(24):7118–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lunetti P, et al. Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes. Febs J. 2019;286(4):688–709.

    Article  CAS  PubMed  Google Scholar 

  70. LeBleu VS, et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16(10):992–1003, 1–15.

  71. Davis RT, et al. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat Cell Biol. 2020;22(3):310–20.

    Article  CAS  PubMed  Google Scholar 

  72. Evans KW, et al. Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple-negative breast cancer. Cancer Res. 2021;81(21):5572–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yap TA, et al. Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors. J Clin Oncol. 2019;37(15_Suppl.):3014.

    Article  Google Scholar 

  74. Cheng C, et al. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 2018;38(1):27.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Rohrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732–49.

    Article  PubMed  Google Scholar 

  76. Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets. 2017;21(11):1001–16.

    Article  CAS  PubMed  Google Scholar 

  77. Li J, et al. Fatty acid synthase mediates the epithelial-mesenchymal transition of breast cancer cells. Int J Biol Sci. 2014;10(2):171–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Alli PM, et al. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene. 2005;24(1):39–46.

    Article  CAS  PubMed  Google Scholar 

  79. Schug ZT, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015;27(1):57–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang Y, et al. Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res. 2003;282(2):132–7.

    Article  CAS  PubMed  Google Scholar 

  81. DeBose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem Sci. 2018;43(5):358–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bao J, et al. SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer. Oncol Lett. 2016;12(4):2409–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. van Weverwijk A, et al. Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation. Nat Commun. 2019;10(1):2698.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ruan C, Meng Y, Song H. CD36: an emerging therapeutic target for cancer and its molecular mechanisms. J Cancer Res Clin Oncol. 2022;148(7):1551–8.

    Article  CAS  PubMed  Google Scholar 

  85. Liang Y, et al. CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells. Oncogenesis. 2018;7(12):98.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Feng WW, et al. CD36-mediated metabolic rewiring of breast cancer cells promotes resistance to HER2-targeted therapies. Cell Rep. 2019;29(11):3405-20.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ligorio F, et al. Predictive role of CD36 expression in HER2-positive breast cancer patients receiving neoadjuvant trastuzumab. J Natl Cancer Inst. 2022;114(12):1720–7.

    Article  PubMed  Google Scholar 

  88. Jovankić JV, et al. Potential of orlistat to induce apoptotic and antiangiogenic effects as well as inhibition of fatty acid synthesis in breast cancer cells. Eur J Pharmacol. 2023;939: 175456.

    Article  PubMed  Google Scholar 

  89. Gruslova A, et al. FASN inhibition as a potential treatment for endocrine-resistant breast cancer. Breast Cancer Res Treat. 2021;187(2):375–86.

    Article  CAS  PubMed  Google Scholar 

  90. Alwarawrah Y, et al. Fasnall, a selective FASN inhibitor, shows potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer. Cell Chem Biol. 2016;23(6):678–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Falchook G, et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021;34: 100797.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Granchi C, et al. A patent review of monoacylglycerol lipase (MAGL) inhibitors (2013–2017). Expert Opin Ther Pat. 2017;27(12):1341–51.

    Article  CAS  PubMed  Google Scholar 

  93. Marino S, et al. Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice. EBioMedicine. 2019;44:452–66.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Lien EC, Lyssiotis CA, Cantley LC. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Recent Results Cancer Res. 2016;207:39–72.

    Article  CAS  PubMed  Google Scholar 

  95. Pereira B, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pearce ST, Jordan VC. The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol. 2004;50(1):3–22.

    Article  PubMed  Google Scholar 

  97. Iwao K, et al. Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction. Cancer. 2000;89(8):1732–8.

    Article  CAS  PubMed  Google Scholar 

  98. Wurster M, et al. Evaluation of ERalpha, PR and ERbeta isoforms in neoadjuvant treated breast cancer. Oncol Rep. 2010;24(3):653–9.

    CAS  PubMed  Google Scholar 

  99. Choi Y. Estrogen receptor beta expression and its clinical implication in breast cancers: favorable or unfavorable? J Breast Cancer. 2022;25(2):75–93.

    Article  PubMed  PubMed Central  Google Scholar 

  100. O’Mahony F, et al. Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells. Mol Endocrinol. 2012;26(12):2058–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang J, et al. Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer. Proc Natl Acad Sci USA. 2015;112(49):15172–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jia M, et al. Estrogen receptor α promotes breast cancer by reprogramming choline metabolism. Cancer Res. 2016;76(19):5634–46.

    Article  CAS  PubMed  Google Scholar 

  103. Leygue E, Murphy LC. A bi-faceted role of estrogen receptor β in breast cancer. Endocr Relat Cancer. 2013;20(3):R127–39.

    Article  CAS  PubMed  Google Scholar 

  104. Elebro K, et al. High estrogen receptor β expression is prognostic among adjuvant chemotherapy-treated patients: results from a population-based breast cancer cohort. Clin Cancer Res. 2017;23(3):766–77.

    Article  CAS  PubMed  Google Scholar 

  105. Chang J, et al. Expression of ERβ gene in breast carcinoma and the relevance in neoadjuvant therapy. Oncol Lett. 2017;13(3):1641–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhou Z, Zhou J, Du Y. Estrogen receptor beta interacts and colocalizes with HADHB in mitochondria. Biochem Biophys Res Commun. 2012;427(2):305–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ma R, et al. Estrogen receptor β as a therapeutic target in breast cancer stem cells. J Natl Cancer Inst. 2017;109(3):1–14.

    Article  PubMed  Google Scholar 

  108. Kaur RP, et al. Role of p53 gene in breast cancer: focus on mutation spectrum and therapeutic strategies. Curr Pharm Des. 2018;24(30):3566–75.

    Article  CAS  PubMed  Google Scholar 

  109. Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med. 2016;6(3): a026104.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Jiang P, et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 2011;13(3):310–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Liu Y, Gu W. The complexity of p53-mediated metabolic regulation in tumor suppression. Semin Cancer Biol. 2021;85:4–32.

    Article  PubMed  Google Scholar 

  112. 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):2627–33.

    Article  CAS  PubMed  Google Scholar 

  113. Zhang C, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.

    Article  PubMed  Google Scholar 

  114. Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. 2012;72(2):560–7.

    Article  CAS  PubMed  Google Scholar 

  115. Chao CH, et al. Mutant p53 attenuates oxidative phosphorylation and facilitates cancer stemness through downregulating miR-200c-PCK2 axis in basal-like breast cancer. Mol Cancer Res. 2021;19(11):1900–16.

    Article  CAS  PubMed  Google Scholar 

  116. Heffernan-Stroud LA, et al. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene. 2012;31(9):1166–75.

    Article  CAS  PubMed  Google Scholar 

  117. Freed-Pastor WA, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148(1–2):244–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hassin O, Oren M. Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2023;22(2):127–44.

  119. Duffy MJ, Synnott NC, Crown J. Mutant p53 in breast cancer: potential as a therapeutic target and biomarker. Breast Cancer Res Treat. 2018;170(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  120. Ali D, et al. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur J Haematol. 2011;86(3):206–15.

    Article  CAS  PubMed  Google Scholar 

  121. Makhale A, et al. CX-5461 enhances the efficacy of APR-246 via induction of DNA damage and replication stress in triple-negative breast cancer. Int J Mol Sci. 2021;22(11):5782.

  122. Liang Y, et al. APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice. Breast Cancer. 2019;11:249–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Cluzeau T, et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myelodysplasies (GFM). J Clin Oncol. 2021;39(14):1575–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Xu J, Chen Y, Olopade OI. MYC and breast cancer. Genes Cancer. 2010;1(6):629–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Blancato J, et al. Correlation of amplification and overexpression of the c-myc oncogene in high-grade breast cancer: FISH, in situ hybridisation and immunohistochemical analyses. Br J Cancer. 2004;90(8):1612–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Roux-Dosseto M, et al. c-Myc gene amplification in selected node-negative breast cancer patients correlates with high rate of early relapse. Eur J Cancer. 1992;28a(10):1600–4.

    Article  CAS  PubMed  Google Scholar 

  127. Mo H, et al. S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer. Mol Cancer. 2022;21(1):171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shen L, et al. Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci U S A. 2015;112(17):5425–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Camarda R, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med. 2016;22(4):427–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bott AJ, et al. Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation. Cell Metab. 2015;22(6):1068–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chen Z, et al. 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;149:118–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Jun JC, et al. Hypoxia-inducible factors and cancer. Curr Sleep Med Rep. 2017;3(1):1–10.

    Article  PubMed  PubMed Central  Google Scholar 

  133. de Heer EC, Jalving M, Harris Al. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020;130(10):5074–87.

  134. Bos R, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001;93(4):309–14.

    Article  CAS  PubMed  Google Scholar 

  135. Ramirez-Tortosa CL, et al. Hypoxia-inducible factor-1 alpha expression is predictive of pathological complete response in patients with breast cancer receiving neoadjuvant chemotherapy. Cancers (Basel). 2022;14(21):5393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Laughner E, et al. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21(12):3995–4004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bensaad K, et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 2014;9(1):349–65.

    Article  CAS  PubMed  Google Scholar 

  138. Lu H, et al. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci USA. 2015;112(33):E4600–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yu B, et al. Pseudolaric acid B-driven phosphorylation of c-Jun impairs its role in stabilizing HIF-1alpha: a novel function-converter model. J Mol Med (Berl). 2012;90(8):971–81.

    Article  CAS  PubMed  Google Scholar 

  140. Yu J, et al. Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death. Oncol Lett. 2016;11(3):1731–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ghosh R, et al. Targeting HIF-1alpha by natural and synthetic compounds: a promising approach for anti-cancer therapeutics development. Molecules. 2022;27(16):5192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Jones DT, Harris AL. Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol Cancer Ther. 2006;5(9):2193–202.

    Article  CAS  PubMed  Google Scholar 

  143. Xiang L, et al. Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med (Berl). 2014;92(2):151–64.

    Article  CAS  PubMed  Google Scholar 

  144. Jhaveri K, et al. A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res. 2017;19(1):89.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Woo YM, et al. Inhibition of aerobic glycolysis represses Akt/mTOR/HIF-1α axis and restores tamoxifen sensitivity in antiestrogen-resistant breast cancer cells. PLoS ONE. 2015;10(7): e0132285.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Ricoult SJ, et al. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene. 2016;35(10):1250–60.

    Article  CAS  PubMed  Google Scholar 

  147. Lien EC, et al. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol. 2016;18(5):572–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32.

    Article  CAS  PubMed  Google Scholar 

  149. Saran U, Foti M, Dufour JF. Cellular and molecular effects of the mTOR inhibitor everolimus. Clin Sci (Lond). 2015;129(10):895–914.

    Article  CAS  PubMed  Google Scholar 

  150. Raphael J, et al. Everolimus in advanced breast cancer: a systematic review and meta-analysis. Target Oncol. 2020;15(6):723–32.

    Article  PubMed  Google Scholar 

  151. Knudsen ES, et al. Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine. Gastroenterology. 2016;150(1):48–63.

    Article  PubMed  Google Scholar 

  152. Westcott PM, To MD. The genetics and biology of KRAS in lung cancer. Chin J Cancer. 2013;32(2):63–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Serebriiskii IG, et al. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat Commun. 2019;10(1):3722.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Santarpia L, et al. Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. Breast Cancer Res Treat. 2012;134(1):333–43.

    Article  CAS  PubMed  Google Scholar 

  155. Hoeflich KP, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–64.

    Article  CAS  PubMed  Google Scholar 

  156. Rinehart J, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22(22):4456–62.

    Article  CAS  PubMed  Google Scholar 

  157. Li JJ, Tsang JT, Tse GM. Tumor microenvironment in breast cancer: updates on therapeutic implications and pathologic assessment. Cancers (Basel). 2021;13(16):4233.

  158. Li J, Wu J, Han J. Analysis of tumor microenvironment heterogeneity among breast cancer subtypes to identify subtype-specific Signatures. Genes (Basel). 2022;14(1):44.

  159. Wang Y, et al. The double-edged roles of ROS in cancer prevention and therapy. Theranostics. 2021;11(10):4839–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kamarajugadda S, et al. Glucose oxidation modulates anoikis and tumor metastasis. Mol Cell Biol. 2012;32(10):1893–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kamarajugadda S, et al. Manganese superoxide dismutase promotes anoikis resistance and tumor metastasis. Cell Death Dis. 2013;4(2): e504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Schito L, Rey S. Hypoxic pathobiology of breast cancer metastasis. Biochim Biophys Acta Rev Cancer. 2017;1868(1):239–45.

    Article  CAS  PubMed  Google Scholar 

  163. Sphyris N, et al. Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth. Oncotarget. 2021;12(8):823–44.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Contreras-Baeza Y, et al. Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. J Biol Chem. 2019;294(52):20135–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sonveaux P, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118(12):3930–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Martínez-Zaguilán R, et al. Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis. 1996;14(2):176–86.

    Article  PubMed  Google Scholar 

  167. Svastová E, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 2004;577(3):439–45.

    Article  PubMed  Google Scholar 

  168. Gilkes DM, et al. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem. 2013;288(15):10819–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed). 2010;15(1):166–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Pavlides S, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009;8(23):3984–4001.

    Article  CAS  PubMed  Google Scholar 

  171. Mercier I, Lisanti MP. Caveolin-1 and breast cancer: a new clinical perspective. Adv Exp Med Biol. 2012;729:83–94.

    Article  CAS  PubMed  Google Scholar 

  172. Ueno T, et al. Characteristic gene expression profiles of human fibroblasts and breast cancer cells in a newly developed bilateral coculture cystem. Biomed Res Int. 2015;2015: 960840.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Lopes-Coelho F, et al. Breast cancer metabolic cross-talk: fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol. 2018;462(Pt B):93–106.

    Article  CAS  PubMed  Google Scholar 

  174. Picon-Ruiz M, et al. Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention. CA Cancer J Clin. 2017;67(5):378–97.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Wu Q, et al. Cancer-associated adipocytes as immunomodulators in cancer. Biomark Res. 2021;9(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Balaban S, et al. Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab. 2017;5:1.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Wang YY, et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight. 2017;2(4): e87489.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Wilczyński JR, Nowak M. Cancer immunoediting: elimination, equilibrium, and immune escape in solid tumors. Exp Suppl. 2022;113:1–57.

    PubMed  Google Scholar 

  179. Brower V. Macrophages: cancer therapy’s double-edged sword. J Natl Cancer Inst. 2012;104(9):649–52.

    Article  PubMed  Google Scholar 

  180. Cai Z, et al. Valproic acid-like compounds enhance and prolong the radiotherapy effect on breast cancer by activating and maintaining anti-tumor immune function. Front Immunol. 2021;12: 646384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Aras S, Zaidi MR. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer. 2017;117(11):1583–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Choi J, et al. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018;33(2):133–45.

    CAS  PubMed  Google Scholar 

  183. Liu D, et al. Comprehensive proteomics analysis reveals metabolic reprogramming of tumor-associated macrophages stimulated by the tumor microenvironment. J Proteome Res. 2017;16(1):288–97.

    Article  CAS  PubMed  Google Scholar 

  184. Lin S, et al. Lactate-activated macrophages induced aerobic glycolysis and epithelial-mesenchymal transition in breast cancer by regulation of CCL5-CCR5 axis: a positive metabolic feedback loop. Oncotarget. 2017;8(66):110426–43.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Chen P, et al. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci U S A. 2017;114(3):580–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Wenes M, et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 2016;24(5):701–15.

    Article  CAS  PubMed  Google Scholar 

  187. Lin B, et al. Tumor-infiltrating lymphocytes: warriors fight against tumors powerfully. Biomed Pharmacother. 2020;132: 110873.

    Article  CAS  PubMed  Google Scholar 

  188. Adams S, et al. 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):2959–66.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Mao Y, et al. The prognostic value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis. PLoS ONE. 2016;11(4): e0152500.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Leong PP, et al. Phenotyping of lymphocytes expressing regulatory and effector markers in infiltrating ductal carcinoma of the breast. Immunol Lett. 2006;102(2):229–36.

    Article  CAS  PubMed  Google Scholar 

  191. Oldford SA, et al. Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients. Int Immunol. 2006;18(11):1591–602.

    Article  CAS  PubMed  Google Scholar 

  192. Zhang Q, et al. CCL5-mediated Th2 immune polarization promotes metastasis in luminal breast cancer. Cancer Res. 2015;75(20):4312–21.

    Article  CAS  PubMed  Google Scholar 

  193. Sakaguchi S, et al. Regulatory T cells and human disease. Annu Rev Immunol. 2020;38:541–66.

    Article  CAS  PubMed  Google Scholar 

  194. Xu L, et al. Enrichment of CCR6+Foxp3+ regulatory T cells in the tumor mass correlates with impaired CD8+ T cell function and poor prognosis of breast cancer. Clin Immunol. 2010;135(3):466–75.

    Article  CAS  PubMed  Google Scholar 

  195. Bates GJ, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.

    Article  PubMed  Google Scholar 

  196. Klysz D, et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal. 2015;8(396):ra97.

    Article  PubMed  Google Scholar 

  197. Kim JY, et al. Glutaminase expression is a poor prognostic factor in node-positive triple-negative breast cancer patients with a high level of tumor-infiltrating lymphocytes. Virchows Arch. 2017;470(4):381–9.

    Article  CAS  PubMed  Google Scholar 

  198. Umansky V, et al. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel). 2016;4(4):36.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Montero AJ, et al. Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer. Breast Cancer Res Treat. 2012;132(1):215–23.

    Article  CAS  PubMed  Google Scholar 

  200. Diaz-Montero CM, et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  201. Boutté AM, et al. Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS ONE. 2011;6(8): e22446.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Jian SL, et al. Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis. 2017;8(5): e2779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Li Y, et al. Recent progress on immunotherapy for breast cancer: tumor microenvironment, nanotechnology and more. Front Bioeng Biotechnol. 2021;9: 680315.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Zhang J, et al. Biochemical aspects of PD-L1 regulation in cancer immunotherapy. Trends Biochem Sci. 2018;43(12):1014–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Mittendorf EA, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Schmid P, et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21.

    Article  CAS  PubMed  Google Scholar 

  207. Cortes J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817–28.

    Article  PubMed  Google Scholar 

  208. Nishimura Y, et al. Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. Cancer Sci. 2015;106(5):505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Li J, et al. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol. 2018;11(1):22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Priceman SJ, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2(+) breast cancer metastasis to the brain. Clin Cancer Res. 2018;24(1):95–105.

    Article  CAS  PubMed  Google Scholar 

  211. Dees S, et al. Emerging CAR-T cell therapy for the treatment of triple-negative breast cancer. Mol Cancer Ther. 2020;19(12):2409–21.

    Article  CAS  PubMed  Google Scholar 

  212. Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016;17(7):451–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Gyamfi J, Kim J, Choi J. Cancer as a metabolic disorder. Int J Mol Sci. 2022;23(3):1155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Cao MD, et al. Metabolic characterization of triple negative breast cancer. BMC Cancer. 2014;14:941.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Fan Y, et al. Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer. Oncotarget. 2016;7(9):9925–38.

    Article  PubMed  PubMed Central  Google Scholar 

  216. Borgan E, et al. Merging transcriptomics and metabolomics: advances in breast cancer profiling. BMC Cancer. 2010;10:628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Xiao Y, et al. Comprehensive metabolomics expands precision medicine for triple-negative breast cancer. Cell Res. 2022;32(5):477–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. His M, et al. Prospective analysis of circulating metabolites and breast cancer in EPIC. BMC Med. 2019;17(1):178.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Playdon MC, et al. Nutritional metabolomics and breast cancer risk in a prospective study. Am J Clin Nutr. 2017;106(2):637–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Moore SC, et al. A metabolomics analysis of body mass index and postmenopausal breast cancer risk. J Natl Cancer Inst. 2018;110(6):588–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Park J, et al. Plasma metabolites as possible biomarkers for diagnosis of breast cancer. PLoS ONE. 2019;14(12): e0225129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Zhao Y, et al. Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Res. 2011;71(13):4585–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Zhou M, et al. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer. 2010;9:33.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Stewart DA, et al. Metabolomics analysis of hormone-responsive and triple-negative breast cancer cell responses to paclitaxel identify key metabolic differences. J Proteome Res. 2016;15(9):3225–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Sugiura A, Rathmell JC. Metabolic barriers to T cell function in tumors. J Immunol. 2018;200(2):400–7.

    Article  CAS  PubMed  Google Scholar 

  226. Chang CH, et al. Metabolic competition in the tumor microenvironment Is a driver of cancer progression. Cell. 2015;162(6):1229–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Ma P, et al. High PD-L1 expression drives glycolysis via an Akt/mTOR/HIF-1α axis in acute myeloid leukemia. Oncol Rep. 2020;43(3):999–1009.

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Zhuoya Jiao and Yunxia Pan contributed equally to this work.

Authors and Affiliations

  1. School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China

    Zhuoya Jiao, Yunxia Pan & Fengyuan Chen

  2. Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China

    Fengyuan Chen

  3. Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China

    Fengyuan Chen

Authors
  1. Zhuoya Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunxia Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fengyuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fengyuan Chen.

Ethics declarations

Funding

This work was supported by Project of High-Level Talents in AHUTCM (Project code: DT19200015), the Returned Overseas Chinese Scholars, Anhui Province (2020LXC009), Key Project of Anhui Provincial Department of Education (KJ2021A0603), Cultivation Program of Young Talents in AHUTCM (2021qnyc03), and Young Scientists Fund of Natural Science Foundation of Anhui Province (2208085QH274).

Conflicts of interest

Zhuoya Jiao, Yunxia Pan, and Fengyuan Chen have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for Publication

Not applicable.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Code availability

Not applicable.

Authors’ contributions

FC: conceptualization, writing, review; ZJ: writing, original draft; YP: editing.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiao, Z., Pan, Y. & Chen, F. The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications. Mol Diagn Ther 27, 349–369 (2023). https://doi.org/10.1007/s40291-023-00645-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-023-00645-2

Search

Navigation