Androgen receptor (AR) expression in
estrogen receptor-positive (ER+)
breast cancer (BC) correlates with lower
tumor grade and a better clinical outcome. Additionally, in normal mammary epithelium or ER+ BC preclinical models,
androgens counteract basal/ER-dependent proliferation. Here, we report an additional mechanism, underlining the protective role exerted by AR. Specifically, the activation of intracellular AR upregulates the Bcl-2-family
protein BAD, and TCGA database analyses show that in ER+ BC, BAD expression is associated with better disease-free survival.
Ligand-activated AR influences its own and BAD cellular compartmentalization by enhancing levels in the nucleus, as well as in mitochondrial fractions. In both compartments, BAD exerts unconventional functions. In the nucleus, BAD and AR physically interact and, upon
androgen stimulation, are recruited at the
AP-1 and ARE sites within the
cyclin D1 promoter region, contributing to explaining the anti-proliferative effect of
androgens in BC cells.
Androgens cause an enrichment in BAD and AR content in the mitochondria, correlated with a decrease in mitochondrial function. Thus, we have defined a novel mechanism by which
androgens modulate BAD expression, its mitochondria localization, and nuclear content to force its ability to act as a cell cycle inhibitor, strengthening the protective role of
androgen signaling in
estrogen-responsive BCs.