Skip to main content

Advertisement

SpringerLink
Log in

Prognostic significance of phosphoglycerate dehydrogenase in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Breast cancer is the most common type of cancer affecting women worldwide. Phosphoglycerate dehydrogenase (PHGDH) is an oxidoreductase in the serine biosynthesis pathway. Although it has been reported to affect growth of various tumors, its role in breast cancer is largely unknown. This study aimed to analyze the expression of PHGDH in breast cancer tissue samples and to determine if PHGDH regulates breast cancer cell proliferation.

Methods

Tissue microarrays consisting of 305 cases of breast invasive ductal carcinoma were used for immunohistochemical evaluation of PHGDH expression. The role of PHGDH in breast cancer was investigated in vitro by knocking down its expression and determining the effect on cell proliferation and cell cycling, and in ovo by using a chorioallantoic membrane (CAM) assay.

Results

Immunohistochemical examination showed that PHGDH is mainly localized in the cytoplasm of breast cancer cells and significantly associated with higher cancer grade, larger tumor size, increased PCNA expression, and lymph node positivity. Analysis of the GOBO dataset of 737 patients demonstrated that increased PHGDH expression was associated with poorer overall survival. Knockdown of PHGDH expression in breast cancer cells in vitro resulted in a decrease in cell proliferation, reduction in cells entering the S phase of the cell cycle, and downregulation of various cell cycle regulatory genes. The volume of breast tumor in an in ovo CAM assay was found to be smaller when PHGDH was silenced.

Conclusion

The findings suggest that PHGDH has a regulatory role in breast cancer cell proliferation and may be a potential prognostic marker and therapeutic target in 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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  2. National Registry of Diseases Office (2017) Singapore Cancer Registry Annual Registry Report 2015. Singapore, Health Promotion Board

    Google Scholar 

  3. Mattaini KR, Sullivan MR, Vander Heiden MG (2016) The importance of serine metabolism in cancer. J Cell Biol 214:249–257

    Article  CAS  Google Scholar 

  4. Hamanaka RB, Chandel NS (2012) Targeting glucose metabolism for cancer therapy. J Exp Med 209:211–215

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43:869–874

    Article  CAS  Google Scholar 

  7. 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 (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476:346–350

    Article  CAS  Google Scholar 

  8. Mullarky E, Mattaini KR, Vander Heiden MG, Cantley LC, Locasale JW (2011) PHGDH amplification and altered glucose metabolism in human melanoma. Pigment Cell Melanoma Res 24:1112–1115

    Article  CAS  Google Scholar 

  9. Zogg CK (2014) Phosphoglycerate dehydrogenase: potential therapeutic target and putative metabolic oncogene. J Oncol 2014:524101

    Article  Google Scholar 

  10. Bleicher RJ (2018) Timing and delays in breast cancer evaluation and treatment. Ann Surg Oncol 25:2829–2838

    Article  Google Scholar 

  11. Hueman MT, Wang H, Yang CQ, Sheng L, Henson DE, Schwartz AM, Chen D (2018) Creating prognostic systems for cancer patients: A demonstration using breast cancer. Cancer Med 7:3611–3621

    Article  Google Scholar 

  12. Yin L, Duan JJ, Bian XW, Yu SC (2020) Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res 22:61

    Article  Google Scholar 

  13. Yu YN, Yip GW, Tan PH, Thike AA, Matsumoto K, Tsujimoto M, Bay BH (2010) Y-box binding protein 1 is up-regulated in proliferative breast cancer and its inhibition deregulates the cell cycle. Int J Oncol 37:483–492

    PubMed  CAS  Google Scholar 

  14. Koo CY, Bay BH, Lui PC, Tse GM, Tan PH, Yip GW (2006) Immunohistochemical expression of heparan sulfate correlates with stromal cell proliferation in breast phyllodes tumors. Mod Pathol 19:1344–1350

    Article  CAS  Google Scholar 

  15. Ringner M, Fredlund E, Hakkinen J, Borg A, Staaf J (2011) GOBO: gene expression-based outcome for breast cancer online. PLoS ONE 6:e17911

    Article  CAS  Google Scholar 

  16. Tan XF, Teo WX, Yip GW (2019) In vitro evaluation of candidate gene targets for cancer therapy. Methods Mol Biol 1974:21–30

    Article  CAS  Google Scholar 

  17. Guo CH, Koo CY, Bay BH, Tan PH, Yip GW (2007) Comparison of the effects of differentially sulphated bovine kidney- and porcine intestine-derived heparan sulphate on breast carcinoma cellular behaviour. Int J Oncol 31:1415–1423

    PubMed  CAS  Google Scholar 

  18. Sys GM, Lapeire L, Stevens N, Favoreel H, Forsyth R, Bracke M, De Wever O (2013) The in ovo CAM-assay as a xenograft model for sarcoma. J Vis Exp 77:e50522

    Google Scholar 

  19. Lokman NA, Elder AS, Ricciardelli C, Oehler MK (2012) Chick chorioallantoic membrane (CAM) assay as an in vivo model to study the effect of newly identified molecules on ovarian cancer invasion and metastasis. Int J Mol Sci 13:9959–9970

    Article  CAS  Google Scholar 

  20. Li CI, Daling JR, Malone KE (2003) Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 21:28–34

    Article  CAS  Google Scholar 

  21. Song Z, Feng C, Lu Y, Lin Y, Dong C (2018) PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer. Gene 642:43–50

    Article  CAS  Google Scholar 

  22. Zhang B, Zheng A, Hydbring P, Ambroise G, Ouchida AT, Goiny M, Vakifahmetoglu-Norberg H, Norberg E (2017) PHGDH defines a metabolic subtype in lung adenocarcinomas with poor prognosis. Cell Rep 19:2289–2303

    Article  CAS  Google Scholar 

  23. Jia XQ, Zhang S, Zhu HJ, Wang W, Zhu JH, Wang XD, Qiang JF (2016) Increased expression of PHGDH and prognostic significance in colorectal cancer. Transl Oncol 9:191–196

    Article  Google Scholar 

  24. Herrmann A, Moss D, See V (2016) The chorioallantoic membrane of the chick embryo to assess tumor formation and metastasis. Methods Mol Biol 1464:97–105

    Article  CAS  Google Scholar 

  25. Nowak-Sliwinska P, Segura T, Iruela-Arispe ML (2014) The chicken chorioallantoic membrane model in biology, medicine and bioengineering. Angiogenesis 17:779–804

    Article  CAS  Google Scholar 

  26. Li M, Pathak RR, Lopez-Rivera E, Friedman SL, Aguirre-Ghiso JA, Sikora AG (2015) The in ovo chick chorioallantoic membrane (CAM) assay as an efficient xenograft model of hepatocellular carcinoma. J Vis Exp 104:52411

    Google Scholar 

  27. Unterlass JE, Basle A, Blackburn TJ, Tucker J, Cano C, Noble MEM, Curtin NJ (2018) Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer. Oncotarget 9:13139–13153

    Article  Google Scholar 

  28. Patani N, Martin LA (2014) Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer. Mol Cell Endocrinol 382:683–694

    Article  CAS  Google Scholar 

  29. Soerjomataram I, Louwman MW, Ribot JG, Roukema JA, Coebergh JW (2008) An overview of prognostic factors for long-term survivors of breast cancer. Breast Cancer Res Treat 107:309–330

    Article  CAS  Google Scholar 

  30. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368

    Article  CAS  Google Scholar 

  31. Murphy CG, Modi S (2009) HER2 breast cancer therapies: a review. Biologics 3:289–301

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363:1938–1948

    Article  CAS  Google Scholar 

  33. Sen U, Chaudhury D, Shenoy PS, Bose B (2021) Differential sensitivities of triple-negative breast cancer stem cell towards various doses of vitamin C: An insight into the internal antioxidant systems. J Cell Biochem 122:349–366

    Article  CAS  Google Scholar 

  34. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861

    Article  CAS  Google Scholar 

  35. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, Investigators IMT (2018) Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 379:2108–2121

    Article  CAS  Google Scholar 

  36. Lucanus AJ, Yip GW (2018) Kinesin superfamily: roles in breast cancer, patient prognosis and therapeutics. Oncogene 37:833–838

    Article  CAS  Google Scholar 

  37. Sheng J, Xue X, Jiang K (2019) Knockdown of kinase family 15 inhibits cancer cell proliferation in vitro and its clinical relevance in triple-negative breast cancer. Curr Mol Med 19:147–155

    Article  CAS  Google Scholar 

  38. Li Q, Qiu J, Yang H, Sun G, Hu Y, Zhu D, Deng Z, Wang X, Tang J, Jiang R (2020) Kinesin family member 15 promotes cancer stem cell phenotype and malignancy via reactive oxygen species imbalance in hepatocellular carcinoma. Cancer Lett 482:112–125

    Article  CAS  Google Scholar 

  39. Lyons TG (2019) Targeted Therapies for Triple-Negative Breast Cancer. Curr Treat Options Oncol 20:82

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by a research Grant NMRC/CIRG/1370/2013 from the National Medical Research Council of Singapore. The authors thank Pei Fern Angele Koh for technical assistance in the CAM Assay.

Author information

Authors and Affiliations

  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore

    Muthukrishnan Chandrika, Pei Jou Chua, Umamaheswari Muniasamy, Cheng Teng Ng, George W. Yip & Boon Huat Bay

  2. Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore

    Aye Aye Thike & Puay Hoon Tan

  3. School of Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Ruby Yun Ju Huang

Authors
  1. Muthukrishnan Chandrika
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pei Jou Chua
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Umamaheswari Muniasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruby Yun Ju Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aye Aye Thike
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng Teng Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Puay Hoon Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. George W. Yip
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Boon Huat Bay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to George W. Yip or Boon Huat Bay.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Ethics approval 2018/2998 (2011/433/F) for the study was obtained from the SingHealth Centralized Institutional Review Board.

Informed consent

Informed consent was waived for this study as only anonymized analysis was performed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chandrika, M., Chua, P.J., Muniasamy, U. et al. Prognostic significance of phosphoglycerate dehydrogenase in breast cancer. Breast Cancer Res Treat 186, 655–665 (2021). https://doi.org/10.1007/s10549-021-06123-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-021-06123-9

Keywords

Search

Navigation