• What is AR?
  • AR in Prostate Cancer
  • AR Amplification
  • Clinical Trials


The androgen receptor (AR) plays a role in the pathogenesis of prostate cancer and can be expressed in invasive breast cancer (Itkonen and Mills 2012; Gonzalez et al 2008). AR is the product of the AR gene, which is located on the X chromosome. AR is in the nuclear receptor superfamily and is part of the steroid receptor family, and it has a six-region structure with a defined functional domain (Itkonen and Mills 2012).

Amplification of the AR gene and AR mutations occur in 30% and 1-30% of castration-resistant prostate cancer, respectively (Waltering et al. 2012). AR expression is measured using immunohistochemistry (IHC), and is detectable in the majority of castration-resistant prostate cancer (Linja et al. 2001; Waltering et al. 2012) and 75% of invasive breast cancers (Collins et al. 2011; Gonzalez et al 2008).

Related Pathways

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2016. AR. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/?tab=0 (Updated September 12).

Last Updated: September 12, 2016

AR (AR) in Prostate Cancer

Targeting the androgen receptor (AR) pathway is the primary focus of most prostate cancer therapeutics. AR signaling is important for the normal development and function of the prostate gland and also plays a clear role in the development and progression of nearly all primary malignancies of the prostate (Lonergan and Tindall 2011; Tan et al. 2015). Androgen deprivation therapy, through surgical or pharmacological castration, has been the primary treatment for prostate cancer for nearly 70 years and is successful at inducing tumor regressions in most patients (Huggins and Hodges 1941; Huggins et al. 1941). However, given long enough, nearly all patients will progress on these therapies to metastatic castration-resistant prostate cancer (mCRPC), an ultimately lethal disease that is no longer sensitive to first-line androgen deprivation therapies (Tan et al. 2015; Watson et al. 2015).

It is now well recognized that mCRPC remains driven by AR signaling (Chen et al. 2004; Watson et al. 2015), and this can occur through both ligand-dependent and ligand-independent means. Mechanisms capable of maintaining AR signaling include tumoral or extragonadal sources of androgens, AR amplification, overexpression, mutations, splice variants, and/or reactivation of the AR through bypass or crosstalk pathways (Graham and Schweizer 2016; Lonergan and Tindall 2011; Watson et al. 2015). Therapeutic strategies to more potently target the AR through AR antagonism (e.g., enzalutamide) or inhibition of androgen synthesis (e.g., abiraterone acetate) have been shown to extend patient survival in randomized Phase 3 clinical trials for patients with CRPC, and these drugs are now in widespread clinical use. However, intrinsic and acquired resistance to these newer more potent AR drugs remains a significant challenge. In most cases, resistance continues to be driven by AR signaling (Imamura and Sadar 2016; Watson et al. 2015), which has led to the development of novel AR-targeting drugs and combination therapies. A subset of CRPC cases may lose dependence on AR signaling, which is often associated with low or absent AR expression and the development of neuroendocrine features (Beltran et al. 2012; Beltran et al. 2016).

The mechanisms underlying primary and acquired resistance to antiandrogen therapies and the role of the AR gene, the AR transcript, and/or the AR protein product are incompletely elucidated. Understanding how AR variations contribute to response and resistance may have prognostic or predictive value towards improving the clinical management of patients with mCRPC (Daniel and Dehm 2016).

Clinical case series combined with supporting preclinical data have suggested that AR amplification, AR overexpression, mutations involving the ligand-binding domain, and AR splice variants are associated with primary and/or acquired resistance to second-generation antiandrogen therapies for mCRPC (Antonarakis et al. 2014; Azad et al. 2015; Carreira et al. 2014; Romanel et al. 2015; Wyatt et al. 2016). Together, AR aberrations are found in ~60% of mCRPC; AR mutations are found in 15–20% of mCRPC cases, and AR copy number gains or amplifications are found in 25–50% (Beltran et al. 2013; Robinson et al. 2015). A recent study reported that patients with a single AR mutation did not exhibit primary resistance to enzalutamide but that patients with multiple AR mutations or amplification showed a worsened progression-free survival, indicative of resistance (Wyatt et al. 2016).

Taxane chemotherapies are also commonly used for the treatment of patients with mCRPC, with docetaxel approved by the FDA in 2004 and cabazitaxel approved in the second line in 2010. Taxanes act through microtubule stabilization, though have also been reported to inhibit AR signaling in mCRPC through suppressed nuclear translocation of the AR protein (Imamura and Sadar 2016). The AR hinge region is important for this effect, and preclinical data suggest that AR splice variants lacking the AR hinge region (e.g., AR-V7) are less sensitive to these therapies (Imamura and Sadar 2016). While expression of AR-V7 has been associated with resistance to abiraterone and enzalutamide, this has not been observed with taxanes (Antonarakis et al. 2015); therefore AR-V7 may represent a treatment selection biomarker. These findings are now undergoing further prospective validation and clinical qualification.

Novel strategies that target (1) the AR N-terminal domain, which is constitutively active in absence of the ligand-binding domain, (2) the AR DNA-binding domain, to diminish AR target gene transcription, (3) co-regulators of the AR pathway, (4) multimodal AR pathway components, or (5) AR variants associated with therapeutic resistance are currently under development along with new antiandrogens (Bambury and Rathkopf 2015; Crona et al. 2015; Culig and Santer 2014; Graham and Schweizer 2016; Imamura and Sadar 2016; Tan et al. 2015).

Contributors: Himisha Beltran, M.D.

Suggested Citation: Beltran, H. 2016. AR (AR) in Prostate Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/ (Updated September 12).

Last Updated: September 12, 2016

AR Amplification in Prostate Cancer

Location of mutation Focal amplification on chromosome Xq12
Frequency of AR amplification in prostate cancer 25–54% (Azad et al. 2015; Beltran et al. 2013; Robinson et al. 2015; Kumar et al. 2016)
Implications for Targeted Therapeutics
Response to hydroxyflutamide Unknown at this timea
Response to bicalutamide Unknown at this timea
Response to enzalutamide Unknown at this timeb
Response to abiraterone Unknown at this timec
Response to galeterone Unknown at this time
Response to other therapies Unknown at this time

Amplification of the AR gene, which encodes the androgen receptor, likely results in increased expression of this receptor and corresponding increasing response to androgen receptor ligands.

aAR amplification is significantly enriched in metastatic castration resistant prostate cancer (mCRPC) compared to primary untreated prostate cancer and is one mechanism of treatment resistance to androgen deprivation therapy (Koivisto et al. 1997; Kahn et al. 2014; Linja et al. 2001; TCGA 2015). AR amplification is linked to progression in mCRPC (Carreira et al. 2014).

b Amplification of the AR gene is associated with decreased response to enzalutamide (Wyatt et al. 2016) and is more common in patients progressing on enzalutamide than on other therapies (Azad et al. 2015).

c A correlation has been found between AR amplification and a lack of response to abiraterone (Carreira et al. 2014; Romanel et al. 2015).

Contributors: Himisha Beltran, M.D.

Suggested Citation: Beltran, H. 2016. AR Amplification in Prostate Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/354/ (Updated September 12).

Last Updated: September 12, 2016

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