BRCA1 IN GENE REGULATION AND TUMOR SUPPRESSION

描述（由申请人提供）：携带易患癌症的BRCA1种系突变的女性一生中患乳腺癌的几率约为80%。此外，30-40%的散发性乳腺癌病例显示BRCA1表达降低，这表明BRCA1功能障碍可能与家族性和散发性乳腺癌有关。虽然BRCA1 DNA修复功能的缺失最有可能导致乳腺癌的发展，但这种缺陷本身可能不足以解释BRCA1相关肿瘤的组织特异性。因此，BRCA1组织特异性肿瘤抑制功能的确切分子基础仍然是一个未解决的问题。据报道，BRCA1与雌激素受体α (ER?)结合并调节其转录活性。强化BRCA1和ER之间的功能联系？我们最近在乳腺癌细胞系中发现了一种新的BRCA1相互作用蛋白（COBRA1），该蛋白与BRCA1共同调节一组常见的雌激素应答基因。也许更有趣的是，我们还发现了BRCA1在脂肪基质细胞（ASCs）中调节雌激素生物合成的新功能。这些发现表明，有必要跳出上皮细胞的“盒子”，阐明BRCA1在乳腺微环境中的功能。因此，我们假设BRCA1通过抑制ER？在乳腺上皮细胞中介导的基因表达和减少脂肪基质细胞中雌激素的产生。多种细胞类型中的BRCA1可能协同抑制乳腺肿瘤的发生。我们提出三个具体目标来检验这一中心假设。目的1和2将研究BRCA1对乳腺癌细胞中雌激素介导的基因表达和脂肪基质细胞（ASCs）中雌激素生物合成的影响。目的3试图通过利用细胞共培养系统和组织特异性Brca1敲除小鼠，整合上皮细胞和基质细胞的研究，研究Brca1在组织/肿瘤微环境中的功能。相关性：BRCA1可能在乳腺微环境中的多种细胞类型中起作用的概念代表了BRCA1研究的概念进步。这些研究的发现有望为开发更有针对性和更有效的brca1相关癌症的预防和治疗策略提供重要指导。

DESCRIPTION (provided by applicant): Women who carry cancer-predisposing germ-line mutations in BRCA1 have approximately 80% chance of developing breast cancer in their lifetime. In addition, 30-40% of sporadic breast cancer cases display reduced BRCA1 expression, suggesting that BRCA1 dysfunction may be associated with both familial and sporadic forms of breast cancer. While loss of the DNA repair function of BRCA1 most likely contributes to breast cancer development, such a defect alone may not be sufficient to explain the tissue-specificity of BRCA1-associated tumors. Thus, the exact molecular basis for the tissue-specific tumor suppressor function of BRCA1 remains an unresolved issue. BRCA1 has been reported to bind to estrogen receptor alpha (ER?) and modulate its transcriptional activity. Reinforcing the functional link between BRCA1 and ER?, we have recently identified a novel BRCA1-interacting protein (COBRA1) that co-regulates a common set of estrogen-responsive genes with BRCA1 in breast carcinoma cell lines. Perhaps more intriguingly, we have also uncovered a new function of BRCA1 in modulation of estrogen biosynthesis in adipose stromal cells (ASCs). These findings point to a need to look outside the "box" of epithelial cells and to elucidate BRCA1 functions in the context of the mammary microenvironment. We therefore hypothesize that BRCA1 blunts estrogen actions by repressing ER?-mediated gene expression in breast epithelial cells and reducing estrogen production in adipose stromal cells. BRCA1 in multiple cell types may act cooperatively to suppress mammary tumorigenesis. We propose three Specific Aims to test this central hypothesis. Aims 1 and 2 will investigate the impacts of BRCA1 on estrogen-mediated gene expression in breast cancer cells and estrogen biosynthesis in adipose stromal cells (ASCs). Aim 3 attempts to integrate the studies of epithelial and stromal cells by utilizing a cell co-culture system and tissue-specific Brca1 knockout mice to study BRCA1 function in the context of the tissue/tumor microenvironment. Relevance: The notion that BRCA1 may function in multiple cell types within the mammary microenvironment represents a conceptual advance in BRCA1 research. Findings from these studies promise to offer important guidance to the development of more targeted and effective strategies for the prevention and treatment of BRCA1-associated cancers.