Androgens Modulate Bcl-2 Agonist of Cell Death (BAD) Expression and Function in Breast Cancer Cells

Abstract

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.

Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer

“…Determination of genes/gene functions specifically responsive to BADSer99 phosphorylation and determining if NCK also affects expression of these genes, or a subset of these genes, or exerts effects separately, may be of utility to determine any potential polypharmacology of NCK. This approach will, however, be complicated by the observation that both non-phosphorylated and phosphorylated BAD exert independent cellular functions 8 and heterodimerization of BAD has been observed with multiple cellular proteins in addition to BCL-2 family members, such as hexokinase 46 , 47 , c-Jun 10 , p53 48 and androgen receptor 49 . The RNA-sequencing and functional analyses contained herein do however suggest that NCK impacts both cancer cell survival and cell cycle, as might be expected 10 , 50 – 52 .…”