Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer

Peters, Amelia A., Buchanan, Grant, Ricciardelli, Carmela, Bianco-Miotto, Tina, Centenera, Margaret M., Harris, Jonathan M., Jindal, Shalini, Segara, Davendra, Jia, Li, Moore, Nicole L., Henshall, Susan M., Birrell, Stephen N., Coetzee, Gerhard A., Sutherland, Robert L., Butler, Lisa M. and Tilley, Wayne D. (2009) Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Research, 69 15: 6131-6140. doi:10.1158/0008-5472.CAN-09-0452

Author Peters, Amelia A.
Buchanan, Grant
Ricciardelli, Carmela
Bianco-Miotto, Tina
Centenera, Margaret M.
Harris, Jonathan M.
Jindal, Shalini
Segara, Davendra
Jia, Li
Moore, Nicole L.
Henshall, Susan M.
Birrell, Stephen N.
Coetzee, Gerhard A.
Sutherland, Robert L.
Butler, Lisa M.
Tilley, Wayne D.
Title Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer
Formatted title
Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2009-08-01
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-09-0452
Volume 69
Issue 15
Start page 6131
End page 6140
Total pages 10
Place of publication United States
Publisher American Association for Cancer Research
Collection year 2010
Language eng
Formatted abstract
There is emerging evidence that the balance between estrogen receptor-α (ERα) 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. AR and ERα 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 ERα-positive disease, with a low level of AR (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 ERα transactivation activity and 17β-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 ERα 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 17β-estradiol on breast cancer cells.
Keyword Estrogen Receptor Alpha
Androgen receptor (AR)
Breast cancer
Disease progression
DNA Binding
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 127 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 19 Apr 2010, 16:41:10 EST by Charna Kovacevic on behalf of School of Pharmacy