BRCA1 and estrogen signaling during tumorigenesis

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In the past year, we have carefully examined ER-alpha expression in our BRCA1 mutant mice. We found that mammary glands of BRCA1 mutant mice displayed higher levels of ER-alpha, and that ER-alpha is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ER-alpha-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ER-alpha signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ER-alpha-signaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.