|Year : 2020 | Volume
| Issue : 2 | Page : 51-54
Androgen receptor: A new player in triple negative breast cancer management
Anurag Mehta1, Atika Dogra2
1 Department of Laboratory, Molecular Diagnostic Services, Rohini, New Delhi, India
2 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
|Date of Submission||08-Dec-2020|
|Date of Acceptance||08-Dec-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Anurag Mehta
Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini 110085, New Delhi.
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mehta A, Dogra A. Androgen receptor: A new player in triple negative breast cancer management. J Curr Oncol 2020;3:51-4
Breast cancer is a diverse group of diseases, comprising entities with distinct morphological appearances and clinical behaviors. It has traditionally been classified based on the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). Breast cancers bereft of any of these predictive markers for targeted therapy are called triple negative breast cancers (TNBCs). Lacking effective genome-directed therapy, this group continues to have inferior survival compared stage to stage with other types of breast cancer, the survival rate at five years being 91% for local, 65% for regional, and 11% for metastatic TNBC. Dissection of the whole gamut of genomic, transcriptomic, epigenomic and miRNA profile is being undertaken at a feverish pitch to identify likely targets for drug development.
The majority of TNBC based on gene expression profiling are separated into basal-like (BL) intrinsic subtypes, but a smaller fraction of non-basal TNBC is also identified. In a seminal work, Lehman et al. subtyped the TNBC into four distinct subtypes: (i) basal-like subtype 1 (BL1) with a defective DNA damage response, (ii) basal-like subtype 2 (BL2) dependent on upregulation of growth factor pathway and expression of myoepithelial markers, (iii) mesenchymal subtype (M) associated with elevated expression of genes involved in cell differentiation and growth factor signaling, and (iv) a luminal androgen subtype characterized by androgen signaling (LAR). The LAR subtype relies on growth stimuli generated by androgen–androgen receptor (AR) binding and has been validated as an authentic subtype in several subsequent studies., The AR is expressed by all the TNBC subtypes but has a pivotal role in LAR subtype. The AR is an emerging biomarker that may have a critical role in the pathogenesis and progression of breast cancer.
| Incidence in Breast Cancer Subtypes|| |
In breast cancer, AR is the most commonly expressed hormone receptor; however, the distribution differs with subtypes. Collins et al. reported that 91% of luminal A, 68% of luminal B, 59% of the HER-2, and 32% of basal-like subtypes show the expression of AR. Compared with other breast cancer subtypes, TNBC generally has a much lower frequency of AR expression. The frequency of AR expression significantly varies in TNBC depending on the study population and ranges from 0% to 53%. A large multi-institutional study has shown that AR expression varied widely among different ethnicities, from 8.3% in the Nigerian cohort of TNBC to 55% in the UK cohort of TNBC. The broad span of AR expression in breast cancer can possibly be attributed to methodology of test, cutoff for positivity, antibody used for staining, and especially the ethnicity of the studied population.
| Role of AR in Breast Cancer Carcinogenesis|| |
The AR is a type I nuclear hormone receptor that remains associated with heat shock proteins in the cytoplasm in the absence of ligand. In the canonical pathway [Figure 1], when androgens attach to AR, conformational changes occur; AR dissociates from heat shock proteins, gets activated, and produces dimers. These dimers move to the nucleus, bind to androgen-responsive elements within target genes, and cause alterations in DNA transcription. The AR dimers can regulate the gene transcription positively or negatively and cause proliferation, differentiation, and apoptosis. In addition, AR can also be stimulated through a noncanonical pathway that modulates AR activity by signal transduction in an ERK-dependent or -independent manner and does not require DNA or RNA interaction.
|Figure 1: Interaction of androgens with androgen receptor in an androgen-responsive environment|
Click here to view
The tumors in the LAR subtype of TNBC show positive staining for AR and are driven by AR signaling. The gene ontologies for the LAR group are highly enriched in hormonally regulated pathways, such as androgen/estrogen metabolic processes and steroid production. The LAR group exhibits increased activity of the AR at transcript level and association with protein levels.
| Prognostic Influence of AR Signaling in TNBC|| |
The effect of AR signaling has been observed to be schizoid, with both tumor-promoting and repressive influences. It may suppress tumors or induce the epithelial-to-mesenchymal transitions and promote metastasis in ER-positive breast cancer. In contrast, AR predominantly promotes the cell proliferation and invasiveness in ER-negative tumors. In TNBC, a plethora of evidence suggest that the AR has antiproliferative effects and is associated with favorable prognosis., Luo et al. have reported the correlation of higher five-year disease-free survival and overall survival in TNBC. The women with AR-negative TNBC had poorer five-year survival rates compared with those with AR-positive TNBC. Another study showed that absence of AR expression was related with increased risk of relapse and distant metastasis in lymph node positive cases of TNBC. Opposing opinion with greater mortality among women with AR-expressing TNBC has also been voiced, though less frequently. Shristi et al. found that AR-positive TNBC reflected superior OS in the US and Nigerian groups, but inferior OS in the cohorts from India, Ireland, and Norway compared with the AR-negative TNBC groups. Another meta-analysis by Gonzalez-Angulo et al. observed better, but, nonsignificant disease-free survival and overall survival; however, others have found either no difference or a negative impact of AR status on outcome.,, In conclusion, the cause behind the divergent actions of AR in TNBC prognosis is still not clear and is likely complex due to the heterogeneity within the group and lack of standardized testing methodology.
| AR as a Therapeutic Target in TNBC|| |
As previously stated, AR can act either as a promoter or as a suppressor in breast carcinogenesis. In this context, both AR agonists and AR antagonists have been investigated for their role in therapeutics. The AR antagonists are being tested in preclinical and clinical studies and are showing encouraging results in the therapy of TNBC.
A phase II clinical trial of the first-generation AR antagonist, bicalutamide, in AR-positive TNBC revealed the first proof of efficacy of AR-targeted therapy. The study showed the clinical benefit rate (CBR) of 19% with a median progression-free survival of 12 weeks. Another phase II clinical trial investigating bicalutamide in metastatic TNBC is ongoing and showed a CBR of 20% (NCT00468715). Enzalutamide, a second-generation AR antagonist evaluated in a phase II clinical trial in AR-positive TNBC, revealed a CBR of 33% at 16 weeks, median OS of 16.5 months, and median PFS of 3.3 months in an evaluable subset of patients. Both AR antagonists have been used as therapy for advanced breast cancer (TNBCs and Tamoxifen-resistant breast cancer), and have shown positive outcomes in clinical trials. Other therapies have been formulated on the use of CYP17A1 inhibitors, such as seviteronel and abiraterone acetate, which target androgen biosynthesis and production, respectively. These inhibitors are being investigated in phase II clinical trials, either alone or in combination with AR antagonists. A few completed/ ongoing trials targeting androgen signaling in TNBC have been detailed in [Table 1]. Such findings suggest that the antagonism of the androgen signaling pathway may possibly be a future therapeutic approach for TNBC. The treatments that target AR allow patients with TNBC to be managed with less toxic endocrine agents, especially patients who are otherwise given nonspecific and cytotoxic drugs. An improved definition of AR positivity, standardization of staining methodologies including use of a validated clone of AR may permit better characterization of the AR-positive group and better realization of a benefit or lack of it from a therapeutic intervention. Further, though there is enough emerging evidence that androgens and the AR signaling pathway are remarkable therapeutic targets for breast cancer, however, the data from abiraterone clinical trials have been a dampener. This may be attributed to the heterogeneity of TNBC where a subtype may respond to AR agonists whereas another subtype might respond to AR antagonists. This necessitates a deeper research and a better understanding of AR action in different forms of breast cancer to effectively use it for greater clinical benefit.
|Table 1: Clinical trials targeting androgen signaling in triple negative breast cancer|
Click here to view
| Conclusion|| |
The AR is a potential target in breast cancer, especially in TNBC, owing to the lack of an effective recognized target. As AR antagonists have been recognized for their inhibitory therapies in prostate cancer, the AR is a “low hanging fruit” in the management of breast cancer. A better patient selection and determining “what to give; and to whom” will be imperative in making an effective use of AR agonists and AR antagonists to improve the breast cancer outcomes. In addition to the routine biomarkers (ER, PR, and HER-2), AR may be used in the clinical assessment of all breast cancers. Finally, AR may have prognostic value in the management of TNBC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Triple-negative breast cancer [Internet]. American Cancer Society; 2020 [cited 2020 Nov 30]. Available from: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-of-breast-cancer/triple-negative.html. [Last accessed on 2020 Dec 4].
Dogra A, Doval DC, Sardana M, Chedi SK, Mehta A Clinicopathological characteristics of triple negative breast cancer at a tertiary care hospital in india. Asian Pac J Cancer Prev 2014;15:10577-83.
Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al
. Refinement of triple-negative breast cancer molecular subtypes: Implications for neoadjuvant chemotherapy selection. PLoS One 2016;11:e0157368.
Yu KD, Zhu R, Zhan M, Rodriguez AA, Yang W, Wong S, et al
. Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res 2013;19:2723-33.
Shah PD, Gucalp A, Traina TA The role of the androgen receptor in triple-negative breast cancer. Womens Health (Lond) 2013;9:351-60.
Anestis A, Zoi I, Papavassiliou AG, Karamouzis MV Androgen receptor in breast cancer—clinical and preclinical research insights. Molecules 2020;25:358.
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;24:924-31.
Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, 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;19:5505-12.
McNamara KM, Yoda T, Takagi K, Miki Y, Suzuki T, Sasano H Androgen receptor in triple negative breast cancer. J Steroid Biochem Mol Biol 2013;133:66-76.
Bhattarai S, Klimov S, Mittal K, Krishnamurti U, Li XB, Oprea-Ilies G, et al
. Prognostic role of androgen receptor in triple negative breast cancer: A multi-institutional study. Cancers (Basel)2019;11:995.
Gerratana L, Basile D, Buono G, De Placido S, Giuliano M, Minichillo S, et al
. Androgen receptor in triple negative breast cancer: A potential target for the targetless subtype. Cancer Treat Rev 2018;68:102-10.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al
. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
Giovannelli P, Di Donato M, Galasso G, Di Zazzo E, Bilancio A, Migliaccio A The androgen receptor in breast cancer. Front Endocrinol (Lausanne) 2018;9:492.
Vera-Badillo FE, Templeton AJ, de Gouveia P, Diaz-Padilla I, Bedard PL, Al-Mubarak M, et al
. Androgen receptor expression and outcomes in early breast cancer: A systematic review and meta-analysis. J Natl Cancer Inst 2014;106: djt319.
McNamara KM, Moore NL, Hickey TE, Sasano H, Tilley WD Complexities of androgen receptor signalling in breast cancer. Endocr Relat Cancer 2014;21:T161-81.
Luo X, Shi YX, Li ZM, Jiang WQ Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer 2010;29:585-90.
Gong Y, Wei W, Wu Y, Ueno NT, Huo L Expression of androgen receptor in inflammatory breast cancer and its clinical relevance. Cancer 2014;120:1775-9.
Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO Prognostic markers in triple-negative breast cancer. Cancer 2007;109:25-32.
Park S, Koo JS, Kim MS, Park HS, Lee JS, Lee JS, et al
. Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. Ann Oncol 2011;22:1755-62.
Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, Carey M, Agarwal R, Meric-Berstam F, et al
. Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res 2009;15:2472-8.
Mrklić I, Pogorelić Z, Capkun V, Tomić S Expression of androgen receptors in triple negative breast carcinomas. Acta Histochem 2013;115:344-8.
Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, et al
. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 2018;36:884-90.
Huang R, Han J, Liang X, Sun S, Jiang Y, Xia B, et al
. Androgen receptor expression and bicalutamide antagonize androgen receptor inhibit β-catenin transcription complex in estrogen receptor-negative breast cancer. Cell Physiol Biochem 2017;43:2212-25.
Arce-Salinas C, Riesco-Martinez MC, Hanna W, Bedard P, Warner E Complete response of metastatic androgen receptor-positive breast cancer to bicalutamide: Case report and review of the literature. J Clin Oncol 2016;34:e21-4.
Narayanan R, Dalton JT Androgen receptor: A complex therapeutic target for breast cancer. Cancers (Basel) 2016;8:108.