The Impact of Androgen Receptor Expression on Breast Cancer Survival: A Retrospective Study and Meta-Analysis

The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC 50 values for the secondgeneration anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.

Section: :4mentioning

confidence: 94%

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

“…subtypes expressing AR and improved OS in ER-positive BCs expressing AR (Qu et al 2013). Conversely, some studies did not report a better outcome (Park et al 2011) or observed an even poorer prognosis (Choi et al 2015) in AR-positive/ER-negative BC.…”

Section: :10mentioning

confidence: 97%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

“…Discrepancies in study results could be explained by multiple factors, including the following: i) the use of tissue microarrays vs whole-tissue sections; ii) use of different AR protein detection techniques (radioligand binding, immunohistochemistry (IHC) or reverse-phase protein array); iii) use of different antibodies for AR immunodetection; iv) measurement of AR mRNA via different platforms in transcriptome profiling studies; v) use of different cut-off scores to define AR positivity and vi) differences in clinical parameters such as sample size, prior treatment regimens, length of follow-up and tumour type. Two recent meta-analyses have reported that AR expression is associated with better breast cancer outcomes (Qu et al 2013, Vera-Badillo et al 2014. However, numerous shortcomings associated with these analyses, most notably the exclusion of several key studies, limit their use in further clarifying the prognostic value of AR.…”

Section: Prognostic Value Of Ar Expression In Breast Cancermentioning

confidence: 99%

Complexities of androgen receptor signalling in breast cancer

McNamara¹,

Moore²,

Hickey³

et al. 2014

123

While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.