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

遗传性乳腺癌基因BRCA 1和BRCA 2的产物参与DMA的修复 通过同源重组的双链断裂（DSB），称为同源定向DNA修复（HDR）。 虽然BRCA 1和BRCA 2的缺失易患乳腺癌，但出现的肿瘤具有明显的 特征，强烈提示肿瘤发生途径的差异。在具体目标#1中，我们将探索 在发育风险期和发育风险期乳腺上皮细胞中DNA损伤反应的方面 致癌应激乳腺发育在增殖周期方面是不寻常的， 这种分化发生在出生后，并因怀孕而大大改变。流行病学研究 人类和啮齿动物致癌物研究强调了妊娠的保护作用。上 作为这一目标的一部分，我们测试了奇偶性是否会导致DNA损伤反应方面的改变。在 第二部分针对这一目的，我们系统地探讨了激活DNA损伤反应所带来的 通过癌基因表达，并评估是否有缺陷的修复修改这种反应。这些研究使 使用在最后一个周期中开发的表达显性干扰肽的转基因小鼠模型， HDR（dnHDR）。这些dnHDR肽是Rad 51的突变形式和干扰BRCA 2 - 1的肽。 Rad 51和BRCA 1-BARD 1相互作用。到目前为止，当dnHDR 在转基因诱导后在小鼠中表达肽。在具体目标#2中，我们将继续 建立和分析dnHDR小鼠群并确定它们的肿瘤组织病理学。一个主要目标是 评估肿瘤进展对持续HDR中断的需求。我们将确定是否共同 可以鉴定不同dnHDR肽的遗传丢失/获得位点。此外，我们会扩大 通过连续肿瘤移植分析肿瘤，以便能够评估额外的遗传变化， 随着持续增长而发生。将评估转移潜力和转录特征。在 具体目标#3，我们计划识别延迟或促进肿瘤的遗传和化疗修饰剂， 当HDR受损时，在乳腺上皮中的发育。肿瘤发生的血管生成要求 将确定HDR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。

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.