The long-term objective of this proposal is to elucidate the mechanism by which BRCA1 suppresses development of breast and ovarian cancers in women. Despite the wealth of evidence that implicates BRCA1 in DNA damage response, it remains unclear as to why loss of BRCA1 function predominantly increases cancer risks in estrogen-responsive tissues. Recent published work and our own preliminary data lead us to the hypothesis that BRCA1 may negatively regulate the tissue-specific expression of aromatase, a rate-limiting enzyme in estrogen biosynthesis and a key player in breast cancer development. Loss of BRCA1 function in ovary and adipose stromal cells in breast tissue may lead to elevated levels of both circulating and local estrogen, thus increasing cancer risks in the major estrogen-responsive tissues. This hypothesis could explain the tissue and gender-specific phenomena of BRCA1. Furthermore, our model predicts that depletion of BRCA1 in ovary or stromal cells in breast tissue may contribute to tumor development in an endocrine or paracrine manner, even when the tumorigenic epithelial cells themselves still retain the functional alleles of BRCA1. This could at least partially explain why somatic mutations of BRCA1 are rarely found in sporadic breast and ovarian cancer. To test this hypothesis, we will study the effect of BRCA1 on aromatase expression by ectopically expression and siRNA knockdown of BRCA1 in tissue culture cells. We will also elucidate the mechanism by which BRCA1 is recruited to the tissue-specific promoter of the aromatase gene. Furthermore, we will investigate the impact of BRCA1 on transcription initiation at the aromatase promoter. Finally we will use mouse models to determine the effect of Brcal on aromatase expression in vivo, circulating estrogen levels, and estrogen-dependent growth in reproductive tissues. The potential link between BRCA1 and aromatase expression represents a conceptual advance in understanding the tumor suppressor function of BRCA1. Given that aromatase inhibitors have become one of the most effective drugs in breast cancer treatment, the proposed work promises to provide novel targets for diagnostic and therapeutic purposes. ? ? ?
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