Modulation of Estrogen Receptor Function by BRCA1

描述（由申请人提供）：我们的长期目标是了解乳腺癌易感基因BRCA 1的失活如何导致乳腺肿瘤发生。在细胞水平上，BRCA1通过将DNA损伤诱导的信号与下游反应偶联，包括DNA损伤修复和细胞周期检查点激活，确保全局基因组稳定性。由于聚集在BRCA1上的DNA损伤诱导的信号传导途径在大多数细胞类型中是保守的，BRCA1可能在维持基因组完整性方面普遍发挥作用。尽管如此，BRCA1的生殖细胞失活主要导致乳腺癌和卵巢癌，其组织限制性肿瘤抑制功能的基础仍然不清楚。最近，我们发现了BRCA1在抑制雌激素受体α（ER α）的配体非依赖性转录活性方面的新功能，ER α是乳房和卵巢生长和分化的主要决定因素。重要的是，我们发现临床验证的BRCA1错义突变消除了这种抑制活性，这表明其ER α特异性抑制功能对BRCA1在乳腺和卵巢肿瘤抑制中的生物活性很重要。在人乳腺癌细胞中，我们观察到BRCA1和ER α在内源性雌激素反应基因启动子之间的关联之前，但不是之后，雌激素刺激。此外，我们证明了雌激素依赖性人卵巢癌细胞中BRCA1的强制减少可能与ER α靶基因的雌激素非依赖性转录和雌激素非依赖性增殖的增加相关。因此，我们假设BRCA1代表一个配体可逆的障碍，转录激活unliganded ER α，并进一步，突变失活BRCA1促进乳腺癌和卵巢上皮细胞增殖，通过雌激素反应基因的异常表达。为了证实和扩展这一假设，我们提出了以下目标。目的1是阐明BRCA 1抑制ER α配体非依赖性转录活性的机制。目的2是表征BRCA1介导的ER α抑制的调节，雌激素依赖性和雌激素非依赖性细胞信号。目的3是通过调节配体非依赖性ER α活性来确定BRCA 1在控制细胞增殖中的生物学作用。这些研究将揭示BRCA1的组织特异性肿瘤抑制功能的新见解，并为未来乳腺癌的干预提供明确的分子靶点。

DESCRIPTION (provided by applicant): Our long-term goal is to understand how inactivation of the breast cancer susceptibility gene, BRCA1, leads to breast tumorigenesis. At the cellular level, BRCA1 ensures global genome stability by coupling DNA damage-induced signals to downstream responses, including DNA damage repair and cell-cycle checkpoint activation. Because the DNA damage-induced signaling pathways that converge on BRCA1 are conserved in most cell types, BRCA1 is likely to function ubiquitously in the maintenance of genome integrity. Nonetheless, germline inactivation of BRCA1 leads principally to cancer of the breast and ovary, and the underlying basis for its tissue-restricted tumor suppressor function remains poorly defined. Recently, we discovered a novel function for BRCA1 in suppressing the ligand-independent transcriptional activity of the estrogen receptor alpha (ERalpha), a principal determinant of the growth and differentiation of breasts and ovaries. Importantly, we showed that clinically validated BRCA1 missense mutations abrogate this repression activity, suggesting that its ERalpha-specific repression function is important for the biological activity of BRCA1 in breast and ovarian tumor suppression. In human breast cancer cells, we observed an association between BRCA1 and ERalpha at endogenous estrogen-responsive gene promoters before, but not after, estrogen stimulation. Furthermore, we demonstrated that forced reduction of BRCA1 in estrogen-dependent human ovarian cancer cells could be correlated with increases in both the estrogen-independent transcription of ERalpha-target genes and estrogen-independent proliferation. We therefore hypothesize that BRCA1 represents a ligand-reversible barrier to transcriptional activation by unliganded ERalpha, and further, that mutational inactivation of BRCA1 promotes breast and ovarian epithelial cell proliferation through aberrant expression of estrogen-responsive genes. To confirm and extend this hypothesis, we propose the following aims. Aim 1 is to elucidate the mechanism by which BRCA1 represses the ligand-independent transcriptional activity of ERalpha. Aim 2 is to characterize the regulation of BRCA1-mediated ERalpha repression by both estrogen-dependent and estrogen-independent cell signals. Aim 3 is to establish the biological role of BRCA1 in the control of cellular proliferation through modulation of ligand-independent ERalpha activity. These studies should reveal novel insight into the tissue-specific tumor suppressor function of BRCA1 and provide defined molecular targets for future intervention in breast cancer.