Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

There is emerging evidence that the balance between estrogen receptor-alpha (ER alpha) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. A.R and ER alpha were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ER alpha-positive disease, with a low level of AIR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ER alpha transactivation activity and 17 beta-estradiol-stimulated growth of breast cancer cells. Transfection of MDA-MB-231. breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ER alpha signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17 beta-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131-40]