Pushing estrogen receptor around in breast cancer

Abstract

The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor–Positive Breast Cancer Models with a Distinct Mechanism of Action

“…S6) and HBCx-22 ( Fig. 2) (9,51). It is conceivable that the varying degree of growth inhibition seen with SARM may be attributed to different ER positivity of these models.…”

MDM2 Inhibition in Combination with Endocrine Therapy and CDK4/6 Inhibition for the Treatment of ER-Positive Breast Cancer

“…For 26 many patients, the disease is treated effectively by surgery and adjuvant endocrine therapy. 27 Unfortunately, ~35% of patients receiving endocrine therapy relapse with resistant disease, either 28 through inherent resistance to treatment or the emergence of acquired endocrine resistance (1,2). 29 Resistant disease that retains ER positivity is typically managed by treating with additional lines 30 of endocrine therapy.…”

Hormone therapy and breast cancer: emerging steroid receptor mechanisms

“…The role of the ER, which exists as two subtypes transcribed from two distinct genes (Kuiper et al 1996, Kuiper & Gustafsson 1997, Enmark & Gustafsson 1999, ER-A and ER-B (Ascenzi et al 2006), has been extensively studied in breast cancer cell biology. Traditionally, estrogens and ER-A were thought to be the main etiological factors contributing to breast cancer pathogenesis, while the PR was considered only as an indicator of a functional ER in breast cancer tumors, implying that the cancer should be sensitive to endocrine-targeting therapies (Horwitz & McGuire 1975, Carroll et al 2016, Lim et al 2016. However, recent studies have highlighted novel roles for the PR in breast cancer cell biology (Daniel et al 2011, Giulianelli et al 2012, Mohammed et al 2015, Singhal et al 2016.…”