BRCA1 IN GENE REGULATION AND TUMOR SUPPRESSION

BRCA1 在基因调控和肿瘤抑制中的作用

• 批准号: 7332037
• 负责人: Rong Li
• 金额: $ 20.29万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7332037
• 关键词: DNA damage; DNA repair; brca gene; breast neoplasms; cell cycle; cell proliferation; cell transformation; cyclins; differential display technique; gel mobility shift assay; gene expression; genetic regulation; genetic regulatory element; immunoprecipitation; intermolecular interaction; neoplasm /cancer genetics; phosphorylation; protein structure function; protooncogene; reporter genes; site directed mutagenesis; southern blotting; tissue /cell culture; transcription factor; transfection; tumor suppressor proteins

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.

描述(由申请人提供)：携带BRCA1致癌胚系突变的女性在一生中有大约80%的机会发展为乳腺癌。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的DNA修复功能的丧失很可能导致乳腺癌的发生，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的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？)并调节其转录活性。为了加强BRCA1和ER？之间的功能联系，我们最近发现了一种新的BRCA1相互作用蛋白(COBRA1)，它在乳腺癌细胞系中与BRCA1共同调节一组常见的雌激素反应基因。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，有必要走出上皮细胞的“盒子”，并在乳腺微环境的背景下阐明BRCA1的功能。因此，我们假设BRCA1通过抑制ER？介导的乳腺上皮细胞基因表达和减少脂肪基质细胞中雌激素的产生来钝化雌激素的作用。BRCA1在多种细胞类型中可能协同作用，抑制乳腺肿瘤的发生。我们提出了三个具体目标来检验这一中心假设。目的1和2将研究BRCA1对乳腺癌细胞雌激素介导的基因表达和脂肪基质细胞(ASCs)雌激素生物合成的影响。目的3尝试利用细胞共培养系统和组织特异性BRCA1基因敲除小鼠整合上皮细胞和基质细胞的研究，以研究BRCA1在组织/肿瘤微环境中的功能。相关性：BRCA1可以在乳腺微环境中的多种细胞类型中发挥作用，这一概念代表了BRCA1研究的概念性进展。这些研究的结果有望为制定更有针对性和更有效的预防和治疗BRCA1相关癌症的战略提供重要指导。