A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation
A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation
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DOI：
10.1038/sj.onc.1210527
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发表时间：
2007-11-08
期刊：
影响因子：
8
通讯作者：
Deng, C-X
中科院分区：
文献类型：
--
作者：
Li, W.;Xiao, C.;Deng, C-X
雌激素及其受体α(ERα)与BRCA1突变相关的组织特异性肿瘤发生有关。然而，在人类BRCA1突变携带者中发生的大多数乳腺癌是ERα阴性的，这挑战了BRCA1和雌激素/ERα在乳腺癌形成中的联系。使用缺乏BRCA1全长形式的小鼠模型，我们在这里表明Era在癌前乳腺和肿瘤发生的初始阶段高表达，尽管它的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ERα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/ERα信号的分子机制，并确定了雌激素/ERα信号级联中的几个关键元件，这些元件可以作为BRCA1相关肿瘤发生的潜在治疗靶点。
Estrogen and its receptor alpha (ER alpha) 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 ER alpha-negative, challenging the link between BRCA1 and estrogen/ER alpha in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa 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.