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

摘要: Estrogen and its receptor alpha (ERalpha) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, majority of breast cancers developed human mutation carriers are ERalpha-negative, challenging link between estrogen/ERalpha cancer formation. Using a mouse model lacking full-length form BRCA1, here we show that ERalpha is highly expressed premalignant mammary gland initiation stages tumorigenesis, although expression gradually diminished during tumor progression. We demonstrate absence increases sensitivity cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation cyclin D1 expression. The turns proliferation ERalpha-positive from paracrine fashion an autocrine or endocrine fashion. Consequently, BRCA1-mutant sensitized cell vitro vivo. These findings illustrate molecular mechanism for signals BRCA1-associated formation, identify several key elements estrogen/ERalpha-signaling cascade can serve as potential therapeutic targets tumorigenesis.