AR Signaling in Breast Cancer

Abstract

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response

“…About 50%-80% of invasive breast cancers (regardless of ER status) express AR and recent studies indicate AR expression is positively associated with a good prognosis. In addition, recent studies showed that AR-expressing triple-negative breast cancer (TNBC) is dependent on AR signaling; thus, targeting AR seems to improve outcomes in TNBC (1)(2)(3)(4)(5)(6)(7). Despite the prevalence and clinical significance of AR expression in breast cancer, preclinical evidence supporting the use of ARtargeting agents and potential biomarkers of response to AR inhibitors in breast cancer are lacking (4).…”

A New Gene Expression Signature for Triple-Negative Breast Cancer using Frozen Fresh Tissue before Neoadjuvant chemotherapy

“…They found diabetes mellitus in TNBC patients, and it has been suggested that hyperglycemia directly regulates AR levels. This observation is of interest for the present study, in patients, making the protein a candidate for targeted therapy, but its prognostic role is not yet clear (40). Recently, downregulation of AR has been associated with Figure 5.…”

Androgen excess in breast cancer development: implications for prevention and treatment

“…Emerging evidence of the role of androgens in the development of ER-negative tumors led to consider AR as a viable therapeutic target. The success of preclinical and clinical trials testing for tolerance and antitumor activity of bicalutamide and enzalutamide provided the foundations for phase II clinical trials investigating a possible use of next generation anti-androgen drugs in breast cancer (Proverbs-Singh et al 2015, Chia et al 2015, Rahim & O'Regan 2017. These trials enrolled both ER-negative patients and ER-positive, resistant to anti-estrogen therapy, patients.…”