[Skip to Content]
[Skip to Content Landing]

Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast CancerA Review

Educational Objective
To learn the role of androgen receptor and the effects of androgen receptor blockade in breast cancer.
1 Credit CME

Importance  The androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments.

Observations  The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor–targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression.

Conclusions and Relevance  Androgen receptor–targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Naoto T. Ueno, MD, PhD, FACP, Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1354, Houston, TX 77030 (nueno@mdanderson.org).

Accepted for Publication: September 12, 2016.

Published Online: March 16, 2017. doi:10.1001/jamaoncol.2016.4975

Author Contributions: Dr Ueno had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kono and Fujii contributed equally to this work.

Concept and design: Kono, Fujii, Ueno.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kono, Fujii, Karuturi, Tripathy.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Tripathy, Ueno.

Study supervision: Kono, Fujii, Lim, Karuturi, Ueno.

Conflict of Interest Disclosures: Dr Karuturi has received research grants from Novartis and AstraZeneca for work unrelated to this manuscript. No other disclosures are reported.

Funding/Support: This work was supported by the Morgan Welch Inflammatory Breast Cancer Research Program; a grant from the State of Texas Rare and Aggressive Breast Cancer Research Program; MD Anderson’s Cancer Center support grant from the National Cancer Institute, CA016672, which supports the Biostatistics Shared Resource; National Cancer Institute grant CA079466; and an award from the Japan Cancer Society.

Role of the Funder/Sponsor: The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Additional Contributions: Stephanie P. Deming, BA, of the Department of Scientific Publications at MD Anderson Cancer Center provided scientific editing services. Greg Pratt, DDS, clinical librarian of the Research Medical Library at MD Anderson Cancer Center, conducted the literature search. They received no additional compensation beyond their regular salaries.

Gucalp  A, Tolaney  S, Isakoff  SJ,  et al; Translational Breast Cancer Research Consortium (TBCRC 011).  Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer.  Clin Cancer Res. 2013;19(19):5505-5512.PubMedGoogle ScholarCrossref
Traina  AT, Miller  K, Yardley  AD,  et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). 2015 ASCO Annual Meeting. Abstract 1003.
Elebro  K, Borgquist  S, Simonsson  M,  et al.  Combined androgen and estrogen receptor status in breast cancer: treatment prediction and prognosis in a population-based prospective cohort.  Clin Cancer Res. 2015;21(16):3640-3650.PubMedGoogle ScholarCrossref
Collins  LC, Cole  KS, Marotti  JD, Hu  R, Schnitt  SJ, Tamimi  RM.  Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study.  Mod Pathol. 2011;24(7):924-931.PubMedGoogle ScholarCrossref
Park  S, Koo  JS, Kim  MS,  et al.  Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers.  Ann Oncol. 2011;22(8):1755-1762.PubMedGoogle ScholarCrossref
Ni  M, Chen  Y, Lim  E,  et al.  Targeting androgen receptor in estrogen receptor-negative breast cancer.  Cancer Cell. 2011;20(1):119-131.PubMedGoogle ScholarCrossref
Yu  Q, Niu  Y, Liu  N,  et al.  Expression of androgen receptor in breast cancer and its significance as a prognostic factor.  Ann Oncol. 2011;22(6):1288-1294.PubMedGoogle ScholarCrossref
Vera-Badillo  FE, Templeton  AJ, de Gouveia  P,  et al.  Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis.  J Natl Cancer Inst. 2014;106(1):djt319.PubMedGoogle ScholarCrossref
Tan  MH, Li  J, Xu  HE, Melcher  K, Yong  EL.  Androgen receptor: structure, role in prostate cancer and drug discovery.  Acta Pharmacol Sin. 2015;36(1):3-23.PubMedGoogle ScholarCrossref
Georget  V, Térouanne  B, Nicolas  JC, Sultan  C.  Mechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor.  Biochemistry. 2002;41(39):11824-11831.PubMedGoogle ScholarCrossref
Lattouf  JB, Srinivasan  R, Pinto  PA, Linehan  WM, Neckers  L.  Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy.  Nat Clin Pract Urol. 2006;3(11):590-601.PubMedGoogle ScholarCrossref
Sarker  D, Reid  AH, Yap  TA, de Bono  JS.  Targeting the PI3K/AKT pathway for the treatment of prostate cancer.  Clin Cancer Res. 2009;15(15):4799-4805.PubMedGoogle ScholarCrossref
Naderi  A, Meyer  M, Dowhan  DH.  Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer.  Neoplasia. 2012;14(4):283-296.PubMedGoogle ScholarCrossref
Schwartz  S, Wongvipat  J, Trigwell  CB,  et al.  Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ.  Cancer Cell. 2015;27(1):109-122.PubMedGoogle ScholarCrossref
Lupien  M, Eeckhoute  J, Meyer  CA,  et al.  FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.  Cell. 2008;132(6):958-970.PubMedGoogle ScholarCrossref
Robinson  JL, Macarthur  S, Ross-Innes  CS,  et al.  Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1.  EMBO J. 2011;30(15):3019-3027.PubMedGoogle ScholarCrossref
Guiu  S, Charon-Barra  C, Vernerey  D,  et al.  Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial.  Future Oncol. 2015;11(16):2283-2297.PubMedGoogle ScholarCrossref
Hu  R, Dawood  S, Holmes  MD,  et al.  Androgen receptor expression and breast cancer survival in postmenopausal women.  Clin Cancer Res. 2011;17(7):1867-1874.PubMedGoogle ScholarCrossref
Panet-Raymond  V, Gottlieb  B, Beitel  LK, Pinsky  L, Trifiro  MA.  Interactions between androgen and estrogen receptors and the effects on their transactivational properties.  Mol Cell Endocrinol. 2000;167(1-2):139-150.PubMedGoogle ScholarCrossref
Cochrane  DR, Bernales  S, Jacobsen  BM,  et al.  Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide.  Breast Cancer Res. 2014;16(1):R7.PubMedGoogle ScholarCrossref
Lønning  PE.  Additive endocrine therapy for advanced breast cancer: back to the future.  Acta Oncol. 2009;48(8):1092-1101.PubMedGoogle ScholarCrossref
Lin  FdeM, Pincerato  KM, Bacchi  CE, Baracat  EC, Carvalho  FM.  Coordinated expression of oestrogen and androgen receptors in HER2-positive breast carcinomas: impact on proliferative activity.  J Clin Pathol. 2012;65(1):64-68.PubMedGoogle ScholarCrossref
Safarpour  D, Pakneshan  S, Tavassoli  FA.  Androgen receptor (AR) expression in 400 breast carcinomas: is routine AR assessment justified?  Am J Cancer Res. 2014;4(4):353-368.PubMedGoogle Scholar
Thike  AA, Yong-Zheng Chong  L, Cheok  PY,  et al.  Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer.  Mod Pathol. 2014;27(3):352-360.PubMedGoogle Scholar
Loibl  S, Müller  BM, von Minckwitz  G,  et al.  Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy.  Breast Cancer Res Treat. 2011;130(2):477-487.PubMedGoogle ScholarCrossref
Lehmann  BD, Bauer  JA, Chen  X,  et al.  Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.  J Clin Invest. 2011;121(7):2750-2767.PubMedGoogle ScholarCrossref
Masuda  H, Baggerly  KA, Wang  Y,  et al.  Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes.  Clin Cancer Res. 2013;19(19):5533-5540.PubMedGoogle ScholarCrossref
Kennedy  BJ.  Fluoxymesterone therapy in advanced breast cancer.  N Engl J Med. 1958;259(14):673-675.PubMedGoogle ScholarCrossref
Parazzini  F, Colli  E, Scatigna  M, Tozzi  L.  Treatment with tamoxifen and progestins for metastatic breast cancer in postmenopausal women: a quantitative review of published randomized clinical trials.  Oncology. 1993;50(6):483-489.PubMedGoogle ScholarCrossref
Ingle  JN, Twito  DI, Schaid  DJ,  et al.  Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer: an updated analysis.  Cancer. 1991;67(4):886-891.PubMedGoogle ScholarCrossref
Birrell  SN, Roder  DM, Horsfall  DJ, Bentel  JM, Tilley  WD.  Medroxyprogesterone acetate therapy in advanced breast cancer: the predictive value of androgen receptor expression.  J Clin Oncol. 1995;13(7):1572-1577.PubMedGoogle ScholarCrossref
Kono  M, Fujii  T, Lyons  RG,  et al.  Impact of androgen receptor expression in fluoxymesterone-treated estrogen receptor–positive metastatic breast cancer refractory to contemporary hormonal therapy.  Breast Cancer Res Treat. 2016;160(1):101-109.Google ScholarCrossref
Narayanan  R, Ahn  S, Cheney  MD,  et al.  Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.  PLoS One. 2014;9(7):e103202.PubMedGoogle ScholarCrossref
Agarwal  N, Di Lorenzo  G, Sonpavde  G, Bellmunt  J.  New agents for prostate cancer.  Ann Oncol. 2014;25(9):1700-1709.PubMedGoogle ScholarCrossref
Masiello  D, Cheng  S, Bubley  GJ, Lu  ML, Balk  SP.  Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor.  J Biol Chem. 2002;277(29):26321-26326.PubMedGoogle ScholarCrossref
Chen  CD, Welsbie  DS, Tran  C,  et al.  Molecular determinants of resistance to antiandrogen therapy.  Nat Med. 2004;10(1):33-39.PubMedGoogle ScholarCrossref
Tran  C, Ouk  S, Clegg  NJ,  et al.  Development of a second-generation antiandrogen for treatment of advanced prostate cancer.  Science. 2009;324(5928):787-790.PubMedGoogle ScholarCrossref
Loriot  Y, Miller  K, Sternberg  CN,  et al.  Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.  Lancet Oncol. 2015;16(5):509-521.PubMedGoogle ScholarCrossref
Elias  AD, Burris  HA, Patel  MR,  et al. MDV3100-08: a phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer. 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P1-16-05. doi:10.1158/1538-7445
Moilanen  AM, Riikonen  R, Oksala  R,  et al.  Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.  Sci Rep. 2015;5:12007.PubMedGoogle ScholarCrossref
Massard  C, Penttinen  HM, Vjaters  E,  et al.  Pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chemotherapy-naive metastatic castration-resistant prostate cancer: an open-label phase 1 study.  Eur Urol. 2016;69(5):834-840.PubMedGoogle ScholarCrossref
Clegg  NJ, Wongvipat  J, Joseph  JD,  et al.  ARN-509: a novel antiandrogen for prostate cancer treatment.  Cancer Res. 2012;72(6):1494-1503.PubMedGoogle ScholarCrossref
Rathkopf  DE, Morris  MJ, Fox  JJ,  et al.  Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.  J Clin Oncol. 2013;31(28):3525-3530.PubMedGoogle ScholarCrossref
Loddick  SA, Ross  SJ, Thomason  AG,  et al.  AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.  Mol Cancer Ther. 2013;12(9):1715-1727.PubMedGoogle ScholarCrossref
Brand  LJ, Olson  ME, Ravindranathan  P,  et al.  EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.  Oncotarget. 2015;6(6):3811-3824.PubMedGoogle ScholarCrossref
Dehm  SM, Tindall  DJ.  Alternatively spliced androgen receptor variants.  Endocr Relat Cancer. 2011;18(5):R183-R196.PubMedGoogle ScholarCrossref
Toren  PJ, Kim  S, Pham  S,  et al.  Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.  Mol Cancer Ther. 2015;14(1):59-69.PubMedGoogle ScholarCrossref
Lehmann  BD, Bauer  JA, Schafer  JM,  et al.  PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors.  Breast Cancer Res. 2014;16(4):406.PubMedGoogle ScholarCrossref
Gonzalez-Angulo  AM, Stemke-Hale  K, Palla  SL,  et al.  Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer.  Clin Cancer Res. 2009;15(7):2472-2478.PubMedGoogle ScholarCrossref
Juric  D, Castel  P, Griffith  M,  et al.  Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.  Nature. 2015;518(7538):240-244.PubMedGoogle ScholarCrossref
Ni  J, Liu  Q, Xie  S,  et al.  Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.  Cancer Discov. 2012;2(5):425-433.PubMedGoogle ScholarCrossref
Carver  BS, Chapinski  C, Wongvipat  J,  et al.  Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.  Cancer Cell. 2011;19(5):575-586.PubMedGoogle ScholarCrossref
Masuda  K, Werner  T, Maheshwari  S,  et al.  Androgen receptor binding sites identified by a GREF_GATA model.  J Mol Biol. 2005;353(4):763-771.PubMedGoogle ScholarCrossref
Wang  Y, He  X, Ngeow  J, Eng  C.  GATA2 negatively regulates PTEN by preventing nuclear translocation of androgen receptor and by androgen-independent suppression of PTEN transcription in breast cancer.  Hum Mol Genet. 2012;21(3):569-576.PubMedGoogle ScholarCrossref
Wang  Y, Yu  Q, He  X, Romigh  T, Altemus  J, Eng  C.  Activation of AR sensitizes breast carcinomas to NVP-BEZ235's therapeutic effect mediated by PTEN and KLLN upregulation.  Mol Cancer Ther. 2014;13(2):517-527.PubMedGoogle ScholarCrossref
Bishop  JL, Sio  A, Angeles  A,  et al.  PD-L1 is highly expressed in Enzalutamide resistant prostate cancer.  Oncotarget. 2015;6(1):234-242.PubMedGoogle ScholarCrossref
Ardiani  A, Farsaci  B, Rogers  CJ,  et al.  Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model.  Clin Cancer Res. 2013;19(22):6205-6218.PubMedGoogle ScholarCrossref
Ward  RD, Weigel  NL.  Steroid receptor phosphorylation: assigning function to site-specific phosphorylation.  Biofactors. 2009;35(6):528-536.PubMedGoogle ScholarCrossref
Gioeli  D, Black  BE, Gordon  V,  et al.  Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization.  Mol Endocrinol. 2006;20(3):503-515.PubMedGoogle ScholarCrossref
Lange  CA, Gioeli  D, Hammes  SR, Marker  PC.  Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer.  Annu Rev Physiol. 2007;69:171-199.PubMedGoogle ScholarCrossref
Wen  Y, Hu  MC, Makino  K,  et al.  HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway.  Cancer Res. 2000;60(24):6841-6845.PubMedGoogle Scholar
Parker  SJ, Peterson  CA, Tudor  CI, Hoffman  J, Uppal  H; University of North Carolina, Chapel Hill; Medivation Inc, San Francisco, CA. A novel biomarker to predict sensitivity to enzalutamide (ENZA) in TNBC. 2015 ASCO Annual Meeting. Abstract 1083.
Cortes  J, Crown  J, Awada  A,  et al. Overall survival (OS) from the phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) signaling inhibitor, in AR+ advanced triple-negative breast cancer (aTNBC). 2015 European Cancer Congress. Abstract 1802.
Watson  PA, Arora  VK, Sawyers  CL.  Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer.  Nat Rev Cancer. 2015;15(12):701-711.PubMedGoogle ScholarCrossref
Azad  AA, Volik  SV, Wyatt  AW,  et al.  Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer.  Clin Cancer Res. 2015;21(10):2315-2324.PubMedGoogle ScholarCrossref
Hu  R, Lu  C, Mostaghel  EA,  et al.  Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer.  Cancer Res. 2012;72(14):3457-3462.PubMedGoogle ScholarCrossref
Antonarakis  ES, Lu  C, Wang  H,  et al.  AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.  N Engl J Med. 2014;371(11):1028-1038.PubMedGoogle ScholarCrossref
Bambury  RM, Louw  J, Krupa  R,  et al.  Characteristics of de novo resistance to androgen targeting therapeutics (AR Tx) through circulating tumor cells (CTCs) analysis in metastatic castration resistant prostate cancer (mCRPC) patients.  Ann Oncol. 2014;25(suppl 4):iv58-iv84. doi:10.1093/annonc/mdu326Google Scholar
Fujii  T,Ruben  JM, Krupa  R,  et al. Androgen receptor expression on circulating tumor cells (CTCs) in metastatic breast cancer. AACR 2016. Section 23, Board No. 13.
Crespo  M, van Dalum  G, Ferraldeschi  R,  et al.  Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents.  Br J Cancer. 2015;112(7):1166-1174.PubMedGoogle ScholarCrossref
Scher  H, Louw  J, Krupa  R,  et al.  Characterization of circulating tumor cells (CTCs) of metastatic castration resistant prostate cancer (mCRPC) patients in first, second & third line systemic therapies.  Ann Oncol. 2014;25(suppl 4):iv58-iv84. doi:10.1093/annonc/mdu326.Google ScholarCrossref
Salvi  S, Casadio  V, Conteduca  V,  et al.  Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone.  Br J Cancer. 2015;112(10):1717-1724.PubMedGoogle ScholarCrossref
Kelvin  J, Lu  D, Parker  D,  et al. Single cell analysis of AR N terminal, AR C terminal and the ARv7 splice variant in the CTCs of metastatic castration resistant prostate cancer (mCRPC) patients. AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA.
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity



My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right