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Tumor Biology

, Volume 37, Issue 6, pp 8159–8168 | Cite as

Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer

  • Tieying Dong
  • Xinmei Kang
  • Zhaoliang Liu
  • Shu Zhao
  • Wenjie Ma
  • Qijia Xuan
  • Hang Liu
  • Zhipeng Wang
  • Qingyuan Zhang
Original Article

Abstract

Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic complete response rate in neoadjuvant chemotherapy breast cancer. However, p53 appears as a protective factor only in the patients receiving neoadjuvant chemotherapy. All the four proteins, PKM2, GFPT1, G6PD and p53, are prognostic markers of breast cancer. The correlation among them suggests that there may be crosstalk of the four proteins in breast cancer.

Keywords

Breast cancer Neoadjuvant chemotherapy Glycolysis Pentose phosphate pathway Hexosamine biosynthetic pathway Prognostic and predictive value 

Notes

Acknowledgments

This study was supported by grant YJSCX2014-49HYD from Harbin Medical University, Harbin, China, The Department of Medical Oncology of the Third Affiliated Hospital of Harbin Medical University, Harbin, China, and the Tumor Research Institute of Heilongjiang, Harbin, China.

Authors’ contributions

Tieying Dong performed IHC experiments, wrote the manuscript, prepared the figures, participated in study design, and interpretation of data. Qijia Xuan prepared the figures and tables. Wenjie Ma collected the information of patients enrolled in this study. Xinmei Kang developed microscopy tools, analyzed specimens, and made a significant contribution to the study design and interpretation of data. Zhaoliang Liu revised the manuscript and polished the language. Shu Zhao and Hang Liu made substantial contributions to review the IHC specimens independently. Zhipeng Wang was involved in critical revisions to the manuscript for important intellectual content. Dr. Qingyuan Zhang participated in the experiment design and interpretation of data. Dr. Qingyuan Zhang gave final approval of the manuscript version to be published and agree to be accountable for questions related to any part of the work. All authors have critically read, edited, and approved the final version of the manuscript.

Compliance with ethical standards

This study was conducted with approval from the Ethics Committee of the Third Affiliated Hospital of Harbin Medical University.

Conflicts of interest

None.

Supplementary material

13277_2015_4729_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 14 kb)
13277_2015_4729_MOESM2_ESM.docx (15 kb)
ESM 2 (DOCX 14 kb)
13277_2015_4729_MOESM3_ESM.png (177 kb)
Supplementary Figure The percentages of positive expression of PKM2, GFPT1, and G6PD in breast cancer group is significantly different from those in relative healthy control group. (PNG 176 kb)

References

  1. 1.
    Ishikawa M, Inoue T, Shirai T, Takamatsu K, Kunihiro S, Ishii H, et al. Simultaneous expression of cancer stem cell-like properties and cancer-associated fibroblast-like properties in a primary culture of breast cancer cells. Cancers. 2014;6(3):1570–8. doi: 10.3390/cancers6031570.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rampurwala MM, Rocque GB, Burkard ME. Update on adjuvant chemotherapy for early breast cancer. Breast Cancer Basic Clin Res. 2014;8:125–33. doi: 10.4137/BCBCR.S9454.Google Scholar
  3. 3.
    Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet (Lond, Engl). 2014;384(9938):164–72. doi: 10.1016/s0140-6736(13)62422-8.CrossRefGoogle Scholar
  4. 4.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74. doi: 10.1073/pnas.191367098.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52. doi: 10.1038/35021093.CrossRefPubMedGoogle Scholar
  6. 6.
    Thompson PA, Brewster AM, Kim-Anh D, Baladandayuthapani V, Broom BM, Edgerton ME, et al. Selective genomic copy number imbalances and probability of recurrence in early-stage breast cancer. PLoS ONE. 2011;6(8):e23543. doi: 10.1371/journal.pone.0023543.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Comprehensive molecular portraits of human breast tumours. Nature. 2012;490 Suppl 7418:61–70. doi: 10.1038/nature11412.
  8. 8.
    Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.CrossRefPubMedGoogle Scholar
  9. 9.
    Gonzalez CD, Alvarez S, Ropolo A, Rosenzvit C, Bagnes MF, Vaccaro MI. Autophagy, Warburg, and Warburg reverse effects in human cancer. BioMed Res Int. 2014;2014:926729. doi: 10.1155/2014/926729.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Chaneton B, Gottlieb E. Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci. 2012;37(8):309–16. doi: 10.1016/j.tibs.2012.04.003.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1alpha-mediated glucose metabolism. Proc Natl Acad Sci U S A. 2014;111(1):279–84. doi: 10.1073/pnas.1311249111.CrossRefPubMedGoogle Scholar
  12. 12.
    Onodera Y, Nam JM, Bissell MJ. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J Clin Invest. 2014;124(1):367–84. doi: 10.1172/JCI63146.CrossRefPubMedGoogle Scholar
  13. 13.
    Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012;45(5):598–609. doi: 10.1016/j.molcel.2012.01.001.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 2012;150(4):685–96. doi: 10.1016/j.cell.2012.07.018.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14(12):1295–304. doi: 10.1038/ncb2629.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Palorini R, Cammarata FP, Balestrieri C, Monestiroli A, Vasso M, Gelfi C, et al. Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein response. Cell Death Dis. 2013;4, e732. doi: 10.1038/cddis.2013.257.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Du W, Jiang P, Mancuso A, Stonestrom A, Brewer MD, Minn AJ, et al. TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol. 2013;15(8):991–1000. doi: 10.1038/ncb2789.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010;330(6009):1340–4. doi: 10.1126/science.1193494.CrossRefPubMedGoogle Scholar
  19. 19.
    Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126(1):107–20. doi: 10.1016/j.cell.2006.05.036.CrossRefPubMedGoogle Scholar
  20. 20.
    Vaughn AE, Deshmukh M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol. 2008;10(12):1477–83. doi: 10.1038/ncb1807.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fico A, Paglialunga F, Cigliano L, Abrescia P, Verde P, Martini G, et al. Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis. Cell Death Differ. 2004;11(8):823–31. doi: 10.1038/sj.cdd.4401420.CrossRefPubMedGoogle Scholar
  22. 22.
    Laderoute KR, Calaoagan JM, Chao WR, Dinh D, Denko N, Duellman S, et al. 5′-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem. 2014;289(33):22850–64. doi: 10.1074/jbc.M114.576371.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sun Y, Gu X, Zhang E, Park MA, Pereira AM, Wang S, et al. Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death Dis. 2014;5, e1231. doi: 10.1038/cddis.2014.204.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012;23(4):352–61. doi: 10.1016/j.semcdb.2012.02.003.CrossRefPubMedGoogle Scholar
  25. 25.
    Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(28):4414–22. doi: 10.1200/JCO.2007.10.6823.CrossRefGoogle Scholar
  26. 26.
    Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. 2012;72(2):560–7. doi: 10.1158/0008-5472.can-11-1215.CrossRefPubMedGoogle Scholar
  27. 27.
    Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312(5780):1650–3. doi: 10.1126/science.1126863.CrossRefPubMedGoogle Scholar
  28. 28.
    Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 2011;13(3):310–6. doi: 10.1038/ncb2172.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gottlieb E. p53 guards the metabolic pathway less travelled. Nat Cell Biol. 2011;13(3):195–7. doi: 10.1038/ncb2177.CrossRefPubMedGoogle Scholar
  30. 30.
    Garber K. Energy deregulation: licensing tumors to grow. Science. 2006;312(5777):1158–9. doi: 10.1126/science.312.5777.1158.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72(1):304–14. doi: 10.1158/0008-5472.can-11-1674.CrossRefPubMedGoogle Scholar
  32. 32.
    Smith-Vikos T. A report of the James Watson lecture at Yale University. Yale J Biol Med. 2012;85(3):417–9.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Flaveny CA, Griffett K, El-Gendy Bel D, Kazantzis M, Sengupta M, Amelio AL, et al. Broad anti-tumor activity of a small molecule that selectively targets the Warburg effect and lipogenesis. Cancer Cell. 2015;28(1):42–56. doi: 10.1016/j.ccell.2015.05.007.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8(10):839–47. doi: 10.1038/nchembio.1060.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lim JY, Yoon SO, Seol SY, Hong SW, Kim JW, Choi SH, et al. Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J Gastroenterol WJG. 2012;18(30):4037–43. doi: 10.3748/wjg.v18.i30.4037.CrossRefPubMedGoogle Scholar
  36. 36.
    van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009. doi: 10.1056/NEJMoa021967.CrossRefPubMedGoogle Scholar
  37. 37.
    Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008;452(7184):181–6. doi: 10.1038/nature06667.CrossRefPubMedGoogle Scholar
  38. 38.
    Lamonte G, Tang X, Chen JL, Wu J, Ding CK, Keenan MM, et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer Metab. 2013;1(1):23. doi: 10.1186/2049-3002-1-23.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science. 2011;334(6060):1278–83. doi: 10.1126/science.1211485.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Harris I, McCracken S, Mak TW. PKM2: a gatekeeper between growth and survival. Cell Res. 2012;22(3):447–9. doi: 10.1038/cr.2011.203.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Tieying Dong
    • 1
  • Xinmei Kang
    • 1
  • Zhaoliang Liu
    • 2
    • 3
  • Shu Zhao
    • 1
  • Wenjie Ma
    • 1
  • Qijia Xuan
    • 1
  • Hang Liu
    • 1
  • Zhipeng Wang
    • 4
  • Qingyuan Zhang
    • 1
    • 3
  1. 1.Department of Internal MedicineThe Third Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Cancer Research InstituteHarbin Medical UniversityHarbinChina
  3. 3.Cancer Research Institute of HeilongjiangHarbinChina
  4. 4.The Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina

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