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

Peters, Amelia, Buchanan, Grant, Ricciardelli, Carmela, Bianco-Miotto, Tina, Centenera, Margaret, Harris, Jonathan, Jindal, Shalini, Segara, Davendra, Jia, Li, Moore, Nicole, Henshall, Susan, Birrell, Stephen, Coetzee, Gerhard, Sutherland, Rob, Butler, Lisa, & Tilley, Wayne (2009) Androgen receptor inhibits estrogen receptor-A activity and is prognostic in breast cancer. Cancer Research, 69(15), pp. 6131-6140.

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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.

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151 citations in Web of Science®
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ID Code: 43084
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Keywords: Androgen, Cancer
DOI: 10.1158/0008-5472.CAN-09-0452
ISSN: 0013-7227
Subjects: Australian and New Zealand Standard Research Classification > AGRICULTURAL AND VETERINARY SCIENCES (070000) > VETERINARY SCIENCES (070700)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100) > Medical Biochemistry - Proteins and Peptides (incl. Medical Proteomics) (110106)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > CLINICAL SCIENCES (110300)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PAEDIATRICS AND REPRODUCTIVE MEDICINE (111400)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 13 Jul 2011 13:09
Last Modified: 15 May 2017 03:35

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