A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation.

Estrogen and its receptor alpha (ERalpha) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERalpha-negative, challenging the link between BRCA1 and estrogen/ERalpha in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERalpha 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 ERalpha-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/ERalpha signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERalpha-signaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.