Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer
There is emerging evidence that the balance between estrogen receptor-alpha (ER?) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed androgen receptor (AR) status in a cohort of 215 invasive ductal breast carcinomas. AR and ER? were co-expressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and Multivariate Cox Regression demonstrated that AR is an independent prognostic factor in ER?-positive disease, with a low level of AR (< 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? transactivation activity and 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? signaling. Consistent with molecular modeling, electrophoretic mobility shift assays demonstrated 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 estradiol on breast cancer cells.
|Authors||Peters, A.A.; Buchanan, G.; Ricciardelli, C.; Bianco-Miotto, T.; Centenera, M.M.; Harris, J.M.; Jindal, S.; Segara, D.; Jia, L.; Moore, N.L.; Henshall, S.M.; Birrell, S.NB.; Coetzee, G.A.; Sutherland, R.L.; Butler, L.M.; Tilley, W.D.|
|Publisher Name||CANCER RESEARCH|
|URL link to publisher's version||http://cancerres.aacrjournals.org/cgi/content/full/69/15/6131|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10148|