Advertisement

Tumor Biology

, Volume 35, Issue 8, pp 8179–8192 | Cite as

Metabolic differences in estrogen receptor-negative breast cancer based on androgen receptor status

  • Songmi Noh
  • Ji-Ye Kim
  • Ja Seung Koo
Research Article

Abstract

This study investigated the relationship between steroid hormone receptor signaling and cellular metabolism in tumorigenesis by examining the expression of metabolic proteins with respect to androgen receptor (AR) and human epidermal growth factor receptor-2 (HER-2) status in estrogen receptor-negative (ER−) breast cancer. ER− breast cancer cases (n = 334) were selected from a microarray analysis, including those that were AR+ and AR− (n = 127 and 207, respectively) and HER-2+ and HER-2− (n = 140 and 194, respectively). The expression of proteins involved in glycolysis, glutaminolysis, and mitochondrial and intermediary (i.e., serine/glycine) metabolism was determined by immunohistochemistry and correlated with AR and HER-2 status. The expression of several proteins involved in glycolysis, glutaminolysis, and serine/glycine metabolism was higher (p < 0.01) in the AR− than in the AR+ group. In the former, the expression of the glycolytic protein carbonic anhydrase (CA)IX was associated with a shorter disease-free survival period (p = 0.029) and overall survival rate (p = 0.001). In a multivariate Cox analysis, immunoreactivity for CAIX (hazard ratio 15.89, 95 % confidence interval (CI) 1.820–131.6; p = 0.010) was an independent factor in predicting the survival of the AR+ group. In conclusion, differential expression patterns of metabolism-related proteins were noted in ER− breast cancer according to AR status. These findings highlight the link between hormone receptor signaling and metabolic pathways whose dysregulation could underlie breast tumorigenesis.

Keywords

Androgen receptor Breast cancer Metabolism 

Notes

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A1002886). This study was supported by a grant from National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1420080).

Conflicts of interest

None

Supplementary material

13277_2014_2103_MOESM1_ESM.doc (50 kb)
Supplementary table 1 Expression of metabolism-related proteins according to AR and HER-2 status in ER − breast cancer (DOC 49 kb)

References

  1. 1.
    Kuenen-Boumeester V, Van der Kwast TH, Claassen CC, Look MP, Liem GS, Klijn JG, et al. The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. Eur J Cancer. 1996;32A(9):1560–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Riva C, Dainese E, Caprara G, Rocca PC, Massarelli G, Tot T, et al. Immunohistochemical study of androgen receptors in breast carcinoma. Evidence of their frequent expression in lobular carcinoma. Virchows Arch. 2005;447(4):695–700.PubMedCrossRefGoogle Scholar
  3. 3.
    Banneau G, Guedj M, MacGrogan G, de Mascarel I, Velasco V, Schiappa R, et al. Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. Breast Cancer Res. 2010;12(4):R63.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene. 2005;24(29):4660–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012;336(6084):1040–4.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Bhargava R, Beriwal S, Striebel JM, Dabbs DJ. Breast cancer molecular class ERBB2: preponderance of tumors with apocrine differentiation and expression of basal phenotype markers CK5, CK5/6, and EGFR. Appl Immunohistochem Mol Morphol. 2010;18(2):113–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476(7360):346–50.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 2012;148(1–2):259–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–95.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013.PubMedCrossRefGoogle Scholar
  11. 11.
    Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Won KY, Kim GY, Kim YW, Song JY, Lim SJ. Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum Pathol. 2010;41(1):107–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Choi J, Jung WH, Koo JS. Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology. 2013;80(1):41–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, et al. GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol. 2011;26(10):1279–86.PubMedGoogle Scholar
  15. 15.
    Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, et al. Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells. Biochem J. 2011;433(1):225–33.PubMedCrossRefGoogle Scholar
  16. 16.
    Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira D, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56(7):860–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Pertega-Gomes N, Vizcaino JR, Miranda-Goncalves V, Pinheiro C, Silva J, Pereira H, et al. Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer. 2011;11:312.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008;452(2):139–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger D, Moreira MA, et al. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol. 2008;27(4):568–74.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim S, do Kim H, Jung WH, Koo JS. Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer. 2013;20(3):339–48.PubMedCrossRefGoogle Scholar
  21. 21.
    Choschzick M, Oosterwijk E, Muller V, Woelber L, Simon R, Moch H, et al. Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer. Virchows Arch. 2011;459(2):193–200.PubMedCrossRefGoogle Scholar
  22. 22.
    Korkeila EA, Sundstrom J, Pyrhonen S, Syrjanen K. Carbonic anhydrase IX, hypoxia-inducible factor-1alpha, ezrin and glucose transporter-1 as predictors of disease outcome in rectal cancer: multivariate Cox survival models following data reduction by principal component analysis of the clinicopathological predictors. Anticancer Res. 2011;31(12):4529–35.PubMedGoogle Scholar
  23. 23.
    Chang H, Shyu KG, Lee CC, Tsai SC, Wang BW, Hsien Lee Y, et al. GL331 inhibits HIF-1alpha expression in a lung cancer model. Biochem Biophys Res Commun. 2003;302(1):95–100.PubMedCrossRefGoogle Scholar
  24. 24.
    Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst. 2003;95(7):516–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Aft RL, Zhang FW, Gius D. Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer. 2002;87(7):805–12.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Mohanti BK, Rath GK, Anantha N, Kannan V, Das BS, Chandramouli BA, et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys. 1996;35(1):103–11.PubMedCrossRefGoogle Scholar
  27. 27.
    Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, et al. Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett. 2003;13(6):1005–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Gallagher SM, Castorino JJ, Wang D, Philp NJ. Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 2007;67(9):4182–9.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of PathologyYonsei University College of MedicineSeoulSouth Korea
  2. 2.Department of Pathology, CHA Gangnam Medical CenterCHA UniversitySeoulSouth Korea

Personalised recommendations