BRCA1 and estrogen signaling during tumorigenesis

在过去的一年里，我们仔细检查了BRCA1突变小鼠的ER-α表达。我们发现BRCA1突变小鼠的乳腺显示出较高水平的ER-α，并且ER-α在癌前病变和肿瘤发生的初始阶段高表达，尽管其表达在乳腺肿瘤进展过程中逐渐减弱。我们证明，缺乏全长BRCA1增加了细胞对雌激素诱导的细胞外信号调节激酶1/2磷酸化和细胞周期蛋白D1表达的敏感性。BRCA1的缺失将ER-α阳性细胞的增殖从旁分泌方式转变为自分泌或内分泌方式。因此，BRCA1突变细胞在体外对雌激素诱导的细胞增殖和在体内的乳腺肿瘤形成是敏感的。这些发现阐明了BRCA1相关组织特异性肿瘤形成中雌激素/ER-α信号的分子机制，并确定了雌激素/ER-α信号级联中的几个关键元件，它们可以作为BRCA1相关肿瘤发生的潜在治疗靶点。

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.