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. 2023 May 8;28(5):383-391.
doi: 10.1093/oncolo/oyad049.

Revisiting Androgen Receptor Signaling in Breast Cancer

Charles Dai  1   2 , Leif W Ellisen  1   2   3
Affiliations

Revisiting Androgen Receptor Signaling in Breast Cancer

Charles Dai et al. Oncologist. .

Abstract

Aberrant estrogen receptor (ER) signaling is central to the pathogenesis of many breast cancers. Like ER, the androgen receptor (AR) is a steroid nuclear receptor that is frequently expressed in breast cancer and has long been considered an attractive therapeutic target. Although androgens were historically employed in the treatment of breast cancer, this strategy has largely fallen out of favor with the advent of modern anti--estrogens, due to virilizing effects from androgens, as well as concerns that androgens could be converted to estrogens to fuel tumor growth. Recent molecular advances, however, including the development of selective androgen receptor modulators, have renewed interest in targeting the AR. Yet androgen signaling in breast cancer remains incompletely understood, and preclinical studies have yielded conflicting and sometimes contradictory evidence regarding the role of AR, resulting in clinical investigations into both AR agonists and antagonists. It is increasingly recognized that AR may very well be context-specific, with divergent actions in ER-positive versus ER-negative disease. Here, we will summarize our current understanding of AR biology and insights from recent investigations into AR-directed therapies in breast cancer.

Keywords: ER-negative; ER-positive; androgen receptor; breast cancer; estrogen receptor.

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Conflict of interest statement

The authors indicated no financial relationships.

Figures

Figure 1.
Figure 1.
Putative models for divergent AR action in ER+ and ER− breast cancer. In ER+ disease, AR may oppose ER by displacing ER from estrogen response elements (EREs) and recruiting ER to androgen response elements (AREs) to inhibit activation of ER-responsive oncogenes. AR may also directly activate AR-responsive tumor suppressor genes as well. Furthermore, in some models of ER blockade and endocrine resistance, AR may also enable proliferation in the absence of ER signaling. In ER− disease, AR may bind differently to activate AR-responsive oncogenes as well as recruit to typically ER-responsive oncogenes to facilitate tumor progression.
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