Regulation of ER by BRCA1 and COBRA1

描述(申请人提供)：乳腺癌是女性最常见的恶性肿瘤，在美国，大约十分之一的女性会在有生之年患上乳腺癌。这项建议的长期目标是研究乳腺癌肿瘤抑制蛋白BRCA1如何有助于预防家族性乳腺癌和卵巢癌。我们目前知识中的一个关键缺陷是理解为什么BRCA1可能是乳腺和卵巢组织特有的，因为BRCA1的突变不会导致其他癌症风险的增加。由于BRCA1在雌激素受体(ER)反应启动子的转录调控中的作用，本项目将研究BRCA1是否具有乳腺和卵巢组织的特异性。雌激素在乳腺肿瘤的发生和发展中起着关键作用。我们已经鉴定出一种蛋白质COBRA1，它与BRCA1和ER相互作用。该项目测试了BRCA1/COBRA1复合体可能被招募到ER反应启动子以抑制转录的假设。该建议的目的之一是确定COBRA1、BRCA1和ER在转录调控中的功能联系。此外，这些研究还将研究COBRA1是否与乳腺癌的发生有关。了解COBRA1的表达如何影响乳腺癌，可能为乳腺癌的分子诊断和治疗提供新的途径。

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy in women and approximately one in ten women in the US will develop breast cancer during her lifetime. The long-term objective of this proposal is to study how the breast cancer tumor suppressor protein, BRCA1, contributes to the prevention of familial breast and ovarian cancers. A key lacuna in our current knowledge is to understand why BRCA1 may be specific for breast and ovary tissues, since mutations in BRCA1 do not result in an increased risk for other cancers. This project will examine whether BRCA1 may be specific for breast and ovary tissues because of its role in transcriptional regulation of estrogen receptor (ER) responsive promoters. Estrogens play a pivotal role in the initiation and progression of breast tumors. We have identified a protein, COBRA1, which interacts with BRCA1 and also with ER. This project tests the hypothesis that a complex of BRCA1/COBRA1 may be recruited to ER responsive promoters to repress transcription. One aim of this proposal is to determine the functional link between COBRA1, BRCA1 and ER in transcriptional regulation. In addition, these studies will examine if COBRA1 contributes to the development of breast cancer. Understanding how COBRA1 expression influences breast cancer may provide new avenues for molecular diagnosis and treatment of breast cancers.