AR pathway activity correlates with AR expression in a HER2-dependent manner and serves as a better prognostic factor in breast cancer
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Androgen receptor (AR) antagonists are currently tested in multiple clinical trials for different breast cancer (BC) subtypes, which emphasizes the need for clarifying the role of AR in this type of cancer. Previous studies showed that AR expression was associated with a favorable prognosis in ER-positive BC. However, the true biological effect of AR signaling in BC is not clear.
An AR pathway signature was generated to compute AR pathway activity in BCs (n = 6439) from 46 microarray datasets. Associations of AR pathway activity and AR expression with BC prognosis were compared by survival analysis.
AR pathway activity showed moderate positive and negative correlations with AR expression in HER2-positive and HER2-negative BCs, respectively. AR pathway activity increased while AR expression decreased in ER-negative BCs. Like ER and progesterone receptor (PR) expression, AR expression was also negatively associated with tumor grade, neoadjuvant response, and recurrence risk in BC. By contrast, AR pathway activity was positively, and more significantly, associated with these clinical features. Moreover, the AR pathway, but not AR expression, was significantly associated with recurrence risk in BC patients treated with endocrine therapy. These data suggest that, although AR expression probably reflects well-differentiated states of BC and is thus associated with favorable prognosis in BC, the biological effects of AR signaling confers worse outcomes in BC.
Our findings encourage the continued evaluation of AR antagonists for BC treatment and support that AR pathway activity serves as a better prognostic factor than AR expression in BC.
KeywordsBreast cancer Androgen receptor pathway Estrogen receptor HER2 Gene signature Endocrine therapy Prognosis prediction
The results here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We are also very grateful to the investigators who contributed the breast cancer microarray datasets that we used in this study.
Compliance with ethical standards
Disclosure of conflict of interest
Bluewater Biotech LLC has filed a provisional patent for the results in this paper. Dingxie Liu has an equity interest in Bluewater Biotech LLC.
- 9.F.E. Vera-Badillo, A.J. Templeton, P. de Gouveia, I. Diaz-Padilla, P.L. Bedard, M. Al-Mubarak, B. Seruga, I.F. Tannock, A. Ocana, E. Amir, Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J. Natl. Cancer Inst. 106, djt319 (2014)PubMedCrossRefPubMedCentralGoogle Scholar
- 10.I. Bozovic-Spasojevic, D. Zardavas, S. Brohée, L. Ameye, D. Fumagalli, F. Ades, E. de Azambuja, Y. Bareche, M. Piccart, M. Paesmans, C. Sotiriou, The prognostic role of androgen receptor in patients with early-stage breast Cancer: A meta-analysis of clinical and gene expression data. Clin. Cancer Res. 23, 2702–2712 (2017)PubMedCrossRefPubMedCentralGoogle Scholar
- 11.K.H. Kensler, E.M. Poole, Y.J. Heng, L.C. Collins, B. Glass, A.H. Beck, A. Hazra, B.A. Rosner, A.H. Eliassen, S.E. Hankinson, E.P. Winer, M. Brown, R.M. Tamimi, Androgen receptor expression and breast Cancer survival: Results from the nurses’ health studies. J. Natl. Cancer Inst. (2018). doi: https://doi.org/10.1093/jnci/djy173 PubMedCentralCrossRefGoogle Scholar
- 12.C.M. Venema, R.D. Bense, T.G. Steenbruggen, H.H. Nienhuis, S.-Q. Qiu, M. van Kruchten, M. Brown, R.M. Tamimi, G.A.P. Hospers, C.P. Schröder, R.S.N. Fehrmann, E.G.E. de Vries, Consideration of breast cancer subtype in targeting the androgen receptor. Pharmacol. Ther. 200, 135–147 (2019)PubMedCrossRefPubMedCentralGoogle Scholar
- 13.F. De Amicis, J. Thirugnansampanthan, Y. Cui, J. Selever, A. Beyer, I. Parra, N.L. Weigel, M.H. Herynk, A. Tsimelzon, M.T. Lewis, G.C. Chamness, S.G. Hilsenbeck, S. Andò, S.A.W. Fuqua, Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res. Treat. 121, 1–11 (2010)PubMedCrossRefPubMedCentralGoogle Scholar
- 15.N.C. D’Amato, M.A. Gordon, B. Babbs, N.S. Spoelstra, K.T.C. Butterfield, K.C. Torkko, V.T. Phan, V.N. Barton, T.J. Rogers, C.A. Sartorius, A. Elias, J. Gertz, B.M. Jacobsen, J.K. Richer, Cooperative dynamics of AR and ER activity in breast Cancer. Mol. Cancer Res. 14, 1054–1067 (2016)PubMedPubMedCentralCrossRefGoogle Scholar
- 17.D.R. Cochrane, S. Bernales, B.M. Jacobsen, D.M. Cittelly, E.N. Howe, N.C. D’Amato, N.S. Spoelstra, S.M. Edgerton, A. Jean, J. Guerrero, F. Gómez, S. Medicherla, I.E. Alfaro, E. McCullagh, P. Jedlicka, K.C. Torkko, A.D. Thor, A.D. Elias, A.A. Protter, J.K. Richer, Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 16, R7 (2014)PubMedPubMedCentralCrossRefGoogle Scholar
- 18.J.R. Sterbis, C. Gao, B. Furusato, Y. Chen, S. Shaheduzzaman, L. Ravindranath, D.J. Osborn, I.L. Rosner, A. Dobi, D.G. McLeod, I.A. Sesterhenn, S. Srivastava, J. Cullen, G. Petrovics, Higher expression of the androgen-regulated gene PSA/HK3 mRNA in prostate Cancer tissues predicts biochemical recurrence-free survival. Clin. Cancer Res. 14, 758–763 (2008)PubMedCrossRefPubMedCentralGoogle Scholar
- 19.A.H. Bild, G. Yao, J.T. Chang, Q. Wang, A. Potti, D. Chasse, M.-B. Joshi, D. Harpole, J.M. Lancaster, A. Berchuck, J.A. Olson, J.R. Marks, H.K. Dressman, M. West, J.R. Nevins, Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353–357 (2006)PubMedCrossRefPubMedCentralGoogle Scholar
- 24.D. Liu, K. Zhou, BRAF/MEK pathway is associated with breast cancer in ER-dependent mode and improves ER status-based cancer recurrence prediction. Clinical Breast Cancer. (2019). doi: https://doi.org/10.1016/j.clbc.2019.08.005
- 30.P. Farmer, H. Bonnefoi, V. Becette, M. Tubiana-Hulin, P. Fumoleau, D. Larsimont, G. Macgrogan, J. Bergh, D. Cameron, D. Goldstein, S. Duss, A.-L. Nicoulaz, C. Brisken, M. Fiche, M. Delorenzi, R. Iggo, Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005)PubMedCrossRefGoogle Scholar
- 35.H.J. Burstein, C. Lacchetti, H. Anderson, T.A. Buchholz, N.E. Davidson, K.A. Gelmon, S.H. Giordano, C.A. Hudis, A.J. Solky, V. Stearns, E.P. Winer, J.J. Griggs, Adjuvant endocrine therapy for women with hormone receptor–positive breast Cancer: ASCO clinical practice guideline focused update. JCO 37, 423–438 (2018)CrossRefGoogle Scholar
- 36.V.K. Arora, E. Schenkein, R. Murali, S.K. Subudhi, J. Wongvipat, M.D. Balbas, N. Shah, L. Cai, E. Efstathiou, C. Logothetis, D. Zheng, C.L. Sawyers, Glucocorticoid receptor confers resistance to Antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013)PubMedPubMedCentralCrossRefGoogle Scholar
- 37.E. G. Bluemn, I. M. Coleman, J. M. Lucas, R. T. Coleman, S. Hernandez-Lopez, R. Tharakan, D. Bianchi-Frias, R. F. Dumpit, A. Kaipainen, A. N. Corella, Y. C. Yang, M. D. Nyquist, E. Mostaghel, A. C. Hsieh, X. Zhang, E. Corey, L. G. Brown, H. M. Nguyen, K. Pienta, M. Ittmann, M. Schweizer, L. D. True, D. Wise, P. S. Rennie, R. L. Vessella, C. Morrissey, and P. S. Nelson, Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling, Cancer Cell 32, 474–489.e6 (2017)PubMedPubMedCentralCrossRefGoogle Scholar
- 44.P. Gasparini, M. Fassan, L. Cascione, G. Guler, S. Balci, C. Irkkan, C. Paisie, F. Lovat, C. Morrison, J. Zhang, A. Scarpa, C.M. Croce, C.L. Shapiro, K. Huebner, Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options. PLoS One 9, e88525 (2014)PubMedPubMedCentralCrossRefGoogle Scholar
- 45.N. Rangel, N. Fortunati, S. Osella-Abate, L. Annaratone, C. Isella, M.G. Catalano, L. Rinella, J. Metovic, R. Boldorini, D. Balmativola, P. Ferrando, F. Marano, P. Cassoni, A. Sapino, I. Castellano, FOXA1 and AR in invasive breast cancer: New findings on their co-expression and impact on prognosis in ER-positive patients. BMC Cancer 18, 703 (2018)PubMedPubMedCentralCrossRefGoogle Scholar
- 47.I. Castellano, E. Allia, V. Accortanzo, A.M. Vandone, L. Chiusa, R. Arisio, A. Durando, M. Donadio, G. Bussolati, A.S. Coates, G. Viale, A. Sapino, Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res. Treat. 124, 607–617 (2010)PubMedCrossRefPubMedCentralGoogle Scholar
- 50.K.H. Kensler, M.M. Regan, Y.J. Heng, G.M. Baker, M.E. Pyle, S.J. Schnitt, A. Hazra, R. Kammler, B. Thürlimann, M. Colleoni, G. Viale, M. Brown, R.M. Tamimi, Prognostic and predictive value of androgen receptor expression in postmenopausal women with estrogen receptor-positive breast cancer: Results from the breast international group trial 1–98. Breast Cancer Res. 21, 30 (2019)PubMedPubMedCentralCrossRefGoogle Scholar