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1 Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States
2 Institute of Genetics, Fudan University, China; Institute of Genetics, Fudan University , China
3 Department of Plastic and Reconstructive Surgery, University of Virginia, Charlottesville, Virginia, United States
* To whom correspondence should be addressed. E-mail: rl2t{at}mac.com.
Adipose tissue provides an important extragonadal source of estrogen. Obesity-associated elevation of estrogen production increases risk of breast cancer in postmenopausal women. Aromatase (Cyp19), which converts androgen to estrogen, is a key enzyme in estrogen biosynthesis. In normal adipose tissue, transcription of the aromatase gene is initiated from a relatively weak adipose-specific promoter (I.4). However, in breast cancer, a switch of promoter utilization from I.4 to a strong ovary-specific promoter PII leads to increased aromatase expression and hence elevated estrogen production. Here we report an intriguing relationship between the breast cancer susceptibility gene BRCA1 and aromatase expression in human adipose stromal cells (ASCs). Upon stimulation by phorbol ester or dexamethasone, increased aromatase expression in ASCs was accompanied by significant reduction of the BRCA1 level. In addition, adipogenesis-induced aromatase expression was also inversely correlated with BRCA1 abundance. Down-regulation of BRCA1 expression in response to various stimuli was through distinct transcription or post-transcription mechanisms. Importantly, siRNA-mediated knockdown of BRCA1 led to specific activation of the breast cancer-associated PII promoter. Therefore, in addition to its well-characterized activities in breast epithelial cells, a role of BRCA1 in modulation of estrogen biosynthesis in ASCs may also contribute to its tissue-specific tumor suppressor function.
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