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Submitted on June 4, 2003
Accepted on October 21, 2003
1 Prince Henry's Institute of Medical Research. 246 Clayton Road, Clayton VIC 3168, AUSTRALIA; Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Victoria 3800, AUSTRALIA
* To whom correspondence should be addressed. E-mail: agnes.kovacic{at}phimr.monash.edu.au.
Estrogen synthesis from C19 precursors is catalyzed by aromatase cytochrome P450. Over-expression of aromatase through atypical promoter usage (use of promoter II) in adipose tissue contributes to breast cancer development and progression. One tumor-derived factor which appears to contribute to this process is prostaglandin E2 (PGE2). A factor that regulates aromatase expression downstream of PGE2 is Liver Receptor Homologue-1 (LRH-1). In a study of factors which inhibit LRH-1, we have examined the ability of short heterodimer partner (SHP) to inhibit aromatase transcription mediated by LRH-1 in preadipocytes. RT-PCR analysis indicated that both LRH-1 and SHP are expressed in human preadipocytes. To assess the effect of SHP on aromatase transcription, a transient transfection system was established using 3T3-L1 preadipocytes. Expression of SHP completely inhibited activity of an aromatase promoter II reporter gene induced by LRH-1. The combined treatment of forskolin and phorbol ester (which mimic PGE2) as well as LRH-1, which maximally induced reporter gene expression (140-fold), was also completely inhibited by SHP. This effect of SHP was mediated by inhibition of LRH-1 transcriptional activity, as measured by activity of GAL4-LRH-1 fusion constructs, and by inhibition of LRH-1 binding to promoter II. We conclude that SHP is a potent inhibitor of aromatase transcription in preadipocytes. Modulation of SHP expression and/or activity in adipose tissue may therefore have significant effects on aromatase expression and estrogen production in breast adipose tissue.
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