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Endocrinology Vol. 140, No. 7 3282-3291
Copyright © 1999 by The Endocrine Society

ARTICLES

Differential Posttranscriptional Regulation of Androgen Receptor Gene Expression by Androgen in Prostate and Breast Cancer Cells1

Bu B. Yeap, Romano G. Krueger and Peter J. Leedman

Laboratory for Cancer Medicine and University Department of Medicine (B.B.Y., P.J.L.), University of Western Australia; Royal Perth Hospital, Perth, Western Australia 6000; Flow Cytometry Unit (R.G.K.), Royal Perth Hospital, Perth, Western Australia 6000

Address all correspondence and requests for reprints to: Dr. Peter J. Leedman, University Department of Medicine, 4th Floor, Medical Research Foundation Building, Rear, 50 Murray Street, Perth, Western Australia 6001. E-mail: peterl{at}cyllene.uwa.edu.au

Androgens, via the androgen receptor (AR), modulate the growth and proliferation of prostate and breast cancer cells. However, the molecular mechanisms underlying the regulation of AR gene expression by androgen in these cells remain to be fully elucidated. To explore differences in AR gene expression between these hormone-responsive tumor cell types, we studied androgen-responsive LNCaP prostate cancer and AR positive MDA453 breast cancer cells. Dihydrotestosterone (DHT) 10 nM increased LNCaP cell proliferation and the proportion of LNCaP cells in S-phase of the cell cycle but inhibited MDA453 cell proliferation and reduced the proportion of MDA453 cells in S-phase of cell cycle. In both these cell lines, DHT decreased total AR messenger RNA (mRNA) but increased AR protein. In LNCaP cells, DHT down-regulated AR mRNA transcription but stabilized AR mRNA. In contrast, in MDA453 cells, DHT had no effect on AR mRNA transcription but destabilized AR mRNA. In summary, transcriptional down-regulation induced by androgens in LNCaP cells results in down-regulation of steady-state AR mRNA despite an androgen-induced increase in AR mRNA stability. However, in MDA453 cells, posttranscriptional destabilization of AR mRNA appears to be the predominant mechanism resulting in down-regulation of AR mRNA by androgen. These results demonstrate cell-specific and divergent regulation of AR mRNA turnover by androgen and identify a novel pathway of androgen-induced posttranscriptional destabilization and down-regulation of AR mRNA in human breast cancer cells. Furthermore, these data establish an important role for posttranscriptional pathways in the regulation of AR gene expression by androgen in human prostate and breast cancer cells.




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