BRCA1 and BRCA2: Homology-Directed DNA Repair and Breast Cancer

BRCA1 和 BRCA2：同源定向 DNA 修复和乳腺癌

• 批准号: 7438487
• 负责人: Maria Jasin
• 金额: $ 46.38万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438487
• 关键词: BRCA1 gene; BRCA2 gene; Birth; Breast Cancer Model; Carcinogens; Characteristics; Cohort Analysis; Collection; DNA Damage; DNA Repair; Defect; Development; Disruption; Dominant-Negative Mutation; Double Strand Break Repair; Doxycycline; Epidemiologic Studies; Gene Expression; Genes; Genetic; Genome; Goals; Growth; Hereditary Breast Carcinoma; Histopathology; Human; Inherited; Laboratories; Lead; Mammary Neoplasms; Mammary gland; Modeling; Mus; Mutate; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; PARP inhibition; Pathway interactions; Peptides; Predisposition; Pregnancy; Risk; Rodent; Role; Signal Transduction; Site; Stress; Testing; Transgenes; Transgenic Organisms; homologous recombination; malignant breast neoplasm; mammary epithelium; mouse model; mutant; parity; protective effect; repaired; response; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

The products of the hereditary breast cancer genes BRCA1 and BRCA2 are involved in the repair of DMA double-strand breaks (DSBs) by homologous recombination, termed homology-directed DNA repair (HDR). Although loss of both BRCA1 and BRCA2 predispose to breast cancer, tumors that arise have distinct characteristics, strongly suggesting differences in tumorigenic pathways. In Specific Aim #1, we will probe aspects of the DNA damage response in mammary epithelium at periods of developmental risk and with oncogenic stress. Mammary gland development is unusual in terms of the cycles of proliferation and differentiation that occur after birth and which are greatly modified by pregnancy. Epidemiologic studies in human and carcinogen studies in rodents have emphasized the protective effect of pregnancy. In the first part of this aim, we test whether parity leads to alterations in aspects of the DNA damage response. In the second part of this aim, we systematically explore the activation of the DNA damage response brought about by oncogene expression and assess whether defective repair modifies this response. These studies make use of transgenic mouse models developed in the last cycle that express dominant-interfering peptides for HDR (dnHDR). These dnHDR peptides are mutant forms of Rad51 and peptides that interfere with BRCA2- Rad51 and BRCA1-BARD1 interaction. Mammary tumors have thus far been observed when dnHDR peptides are expressed in mice following transgene induction. In Specific Aim #2, we will continue to establish and analyze cohorts of dnHDR mice and define their tumor histopathology. A major goal is to assess the requirement for continued HDR disruption for tumor progression. We will determine if common sites of genetic loss/gain can be identified for the different dnHDR peptides. Moreover, we will expand the analysis of tumors by serial tumor grafting, in order to be able to assess additional genetic changes that occur with continued growth. The metastatic potential and transcriptional signature will be assessed. In Specific Aim #3, we plan to identify genetic and chemotherapeutic modifiers that delay or promote tumor development in the mammary epithelium when HDR is impaired. Angiogenic requirements for tumors arising from HDR defects will be determined. Finally, we will examine the effect of HDR disruption on an established oncogene-induced mouse tumor model.

遗传性乳腺癌基因BRCA1和BRCA2的产物参与了DMA的修复 由同源重组引起的双链断裂，称为同源定向DNA修复(HDR)。 虽然BRCA1和BRCA2的缺失都易患乳腺癌，但发生的肿瘤有明显的 特征，强烈提示肿瘤发生途径的不同。在具体目标#1中，我们将探索 发育危险期和高危期乳腺上皮DNA损伤反应的研究 致癌压力。乳腺发育是不寻常的，就增殖周期和 发生在出生后的分化，这种分化会因怀孕而大大改变。年的流行病学研究 人类和啮齿动物致癌物质的研究强调了怀孕的保护作用。在第一个 作为这一目标的一部分，我们测试产次是否会导致DNA损伤反应的某些方面的变化。在 第二部分，我们系统地探讨了DNA损伤反应的激活所带来的 通过癌基因的表达，并评估缺陷修复是否改变了这种反应。这些研究使 使用在上一个周期中开发的表达显性干扰多肽的转基因小鼠模型 HDR(DnHDR)。这些dnHDR多肽是RAD51和干扰BRCA2-2的多肽的突变形式。 RAD51与BRCA1-BARD1相互作用。到目前为止，在dnHDR时观察到了乳腺肿瘤 在转基因诱导后，小鼠体内表达了多肽。在具体目标2中，我们将继续 建立和分析dnhdr小鼠队列，并确定其肿瘤组织病理学。一个主要目标是 评估肿瘤进展需要持续的HDR干扰。我们将确定是否常见 对于不同的dnHDR多肽，可以确定遗传丢失/获得的位置。此外，我们还将扩大 通过连续肿瘤移植对肿瘤进行分析，以便能够评估其他基因变化 随着持续的增长而发生。转移潜能和转录特征将被评估。在……里面 具体目标#3，我们计划识别延缓或促进肿瘤的遗传和化疗修饰物 当HDR受损时，乳腺上皮的发育。肿瘤发生时的血管生成要求 将从HDR中确定缺陷。最后，我们将研究HDR中断对已建立的 癌基因诱导的小鼠肿瘤模型。