BRCA1 Modulates Estrogen Receptor Response in Breast Cancer

BRCA1 调节乳腺癌中的雌激素受体反应

• 批准号: 7148082
• 负责人: Eliot M. Rosen
• 金额: $ 25.02万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148082
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetylation; Address; Adenoviruses; Affect; Alleles; Amino Acids; Androgen Receptor; Animal Model; Apoptosis; Benzo(a)pyrene; Breast; Breast Cancer Prevention; Cancer-Predisposing Gene; Cell Cycle Inhibition; Cell Cycle Progression; Collaborations; Cyclin D1; DNA; DNA Damage; DNA Repair; Depth; Disruption; Down-Regulation; Ductal; E1A-associated p300 protein; EP300 gene; Endometrial; Engineering; Estrogen Receptors; Estrogens; Event; Exhibits; Exons; FOS gene; Figs - dietary; Funding; Generic Drugs; Genes; Genetic Recombination; Genetic Transcription; Genistein; Genomic Instability; Goals; Grant; Growth; Growth Factor; Growth Factor Oncogenes; Hormone Responsive; Human; Human Papillomavirus; Hyperplasia; Hypersensitivity; In Vitro; Indole-3-Carbinol; Inherited; Interferon Gamma Receptor Beta Chain; Investigation; JUN gene; Lead; Ligands; Lysine; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Mammary Tumorigenesis; Mammary gland; Maps; Mediating; Molecular; Mouse Mammary Tumor Virus; Mus; Mutation; Oncogene Proteins; Oncogenes; Oncogenic; PC3 cell line; Pathogenesis; Pathway interactions; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Phytochemical; Progesterone Receptors; Proteins; Publishing; RNA Interference; Rate; Regulation; Repression; Research; Research Personnel; Resistance; Resolution; Risk; Role; Role playing therapy; SV40 T Antigens; Signal Pathway; Signal Transduction; Signaling Protein; Simian virus 40; Site; Somatic Mutation; TP53 gene; Testing; Three-dimensional analysis; Tissues; Transcriptional Activation; Transducers; Transgenic Mice; Tumor Suppression; Up-Regulation; Viral; Wild Type Mouse; breast lesion; c-myc Genes; cancer cell; clinically significant; human ESR1 protein; in vivo; malignant breast neoplasm; mouse model; mutant; novel strategies; prevent; programs; promoter; resistance mechanism; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Background. Inherited mutations of the breast cancer susceptibility gene-1 (BRCA1) confer a high risk for specific tumor types, including breast and ovarian cancers. BRCA1 plays roles in the regulation of DNA repair, cell cycle progression, apoptosis, and gene transcription. But these generic actions do not explain why BRCA1 mutations lead to specific tumor types, such as breast cancer. We have been studying a mammary tissue-specific action of BRCA1 [ie., its ability to repress estrogen receptor (ER-alpha signaling) that may, in part, explain why BRCA1 mutations are associated with estrogen (E2)-dependent tumor types (eg., breast, endometrial, and cervical cancers). Preliminary Studies. During the initial funding period, we have completed and gone beyond the original proposed objectives in understanding the mechanisms by which the BRCA1 regulates estrogen action. In new preliminary studies, we mapped the interacting sites between the BRCA1 and ER-alpha proteins at a high resolution. And we adduced evidence for two distinct mechanisms by which the ER-alpha regulatory function of BRCA1 can be inactivated: 1) through oncogenic signaling pathways (eg., over-expression of cyclin D1, c-Myc, and the c-Akt kinase); and 2) via a tumor-associated mutation of an acetylation site within the hinge region of ER-alpha. Finally, we generated preliminary evidence that exogenous E2 induces mammary hyperplasia and preneoplasia in Brca1-deficient mice. Hypothesis. BRCA1 prevents breast cancer, in part, by inhibition of ER-alpha activity and, in part, by estrogen (E2)-independent actions (ie., by its function as a "caretaker" gene, to prevent genomic instability). The E2-dependent and E2-independent functions of BRCA1 are distinct and can be structurally dissociated. Finally, the ability of BRCA1 to repress ER-alpha can be functionally inactivated by oncoproteins and growth factor signaling pathways. Research Aims. The major goals of this project are: SA1. To precisely identify the molecular determinants of the BRCA1:ER-alpha interaction; SA2. To determine the mechanisms by which oncogene signaling rescues BRCA1 inhibition of ER-alpha. SA3. To determine the role of acetylation in regulating ER-alpha resistance to inhibition by BRCA1; and SA4. To examine the interaction between estrogen and Brca1 in mammary tumorigenesis in vivo. Significance. These studies address a major mechanism by which BRCA1 inactivation leads to breast cancer: namely, deregulation of ER-alpha signaling. They are relevant to the pathogenesis of both hereditary and sporadic breast cancers. Thus, sporadic breast cancers frequently exhibit absent or reduced expression of BRCA1; and we found that knockdown of endogenous BRCA1 by RNA interference causes ligand-independent activation of ER-alpha. In addition to their implications for breast cancer pathogenesis, these studies are of practical importance, since they may suggest novel approaches for breast cancer prevention and treatment.

描述（由申请人提供）：背景。乳腺癌易感性基因1（BRCA1）的遗传突变赋予了特定肿瘤类型的高风险，包括乳腺癌和卵巢癌。 BRCA1在调节DNA修复，细胞周期进程，凋亡和基因转录方面起着作用。但是这些通用作用并不能解释为什么BRCA1突变导致特定的肿瘤类型，例如乳腺癌。我们一直在研究BRCA1的乳腺组织特异性作用[即，它的抑制雌激素受体（ER-Alpha信号传导）的能力，这可能部分解释了为什么BRCA1突变与雌激素（E2）依赖性肿瘤类型相关（例如，乳房，内骨和宫颈癌）。 初步研究。在最初的资金期间，我们已经完成并超越了最初提出的目标，以了解BRCA1调节雌激素作用的机制。在新的初步研究中，我们以高分辨率绘制了BRCA1和ER-Alpha蛋白之间的相互作用位点。我们提出了两个不同机制的证据，通过这些机制，BRCA1的ER-α调节功能可以被灭活：1）通过致癌信号通路（例如，Cyclin D1，C-Myc和C-Akt激酶的过表达）； 2）通过ER-Alpha铰链区域内的乙酰化位点的肿瘤相关突变。最后，我们产生了初步证据，表明外源E2在BRCA1缺陷型小鼠中诱导乳腺增生和乳腺癌。 假设。 BRCA1部分通过抑制ER-Alpha活性，部分地通过雌激素（E2）非依赖性作用（即，其作为“看守”基因的功能，以防止基因组不稳定性）。 BRCA1的E2依赖性和与E2无关的功能是不同的，并且可以在结构上解离。最后，BRCA1抑制ER-α的能力可以在功能上被癌蛋白和生长因子信号传导途径灭活。 研究目的。该项目的主要目标是：SA1。精确地识别BRCA1：ER-Alpha相互作用的分子决定因素； SA2。确定癌基信号挽救BRCA1抑制ER-α的机制。 SA3。确定乙酰化在调节BRCA1抑制ER-Alpha抗性中的作用；和SA4。检查体内乳腺肿瘤发生中雌激素与BRCA1之间的相互作用。 意义。这些研究介绍了BRCA1失活导致乳腺癌的主要机制：即，ER-Alpha信号传导失调。它们与遗传和零星乳腺癌的发病机理有关。因此，零星的乳腺癌经常表现出BRCA1的表达或降低。我们发现，通过RNA干扰对内源性BRCA1敲低会导致ER-α的配体非依赖性激活。除了它们对乳腺癌发病机理的影响外，这些研究也很重要，因为它们可能提出了预防乳腺癌和治疗的新方法。