Human and Murine Models of BRCA1 Tumorigenesis

描述（由申请人提供）：BRCA1用于细胞DNA和重组，尽管需要同源反应损伤，但尚不清楚它在这些关键过程中究竟起什么作用。BRCA1还作为p53应答启动子元件的共激活因子，表明调节介导细胞凋亡和细胞周期的基因表达是这一过程的一部分。然而，考虑到这些细胞过程的普遍性，很难解释BRCA1种系突变女性乳腺癌和其他组织之间癌症风险的显著差异。答案将在于对启动和驱动brcal相关肿瘤发生的事件进行细致的解剖。一个重要的线索是高危组织的激素反应。在上一个资助期，我们开发了一个小鼠模型，该模型概括了已知的与疾病相关的人类种系BRCA1突变，BRCA1的c端有条件缺失。我们将使用该模型来问：哪些遗传事件是brca1相关肿瘤发展所必需的？该提案的具体目的是：目的1：在Brcal BRCT结构域纯合缺失的小鼠中产生小鼠乳腺增生和癌。目的2：通过小鼠和人组织的基因组分析，确定BRCA1相关肿瘤发生的早期遗传变化。目的3：确定雌激素在BRCA1相关乳腺肿瘤的发生和发展中的作用。目的4：评估单倍不全在BRCA1 mut/wt细胞中的作用。这项工作的完成将定义brcal相关癌症中改变的途径，并将确定ER阴性乳腺癌在BRCA1突变女性中占主导地位，是因为它们产生于本质上是ER阴性的细胞，还是因为其他增殖优势取代了ER信号。我们将确定杂合子BRCA1 wt/mut细胞是否比BRCA1 wt/wt细胞具有更高的突变率，以及如果存在这种效应，雌激素是否会增强这种效应。对这些事件的全面了解将为BRCA1突变女性的预防、早期诊断和治疗提供可测试的策略，并增强对一般驱动癌症发展的分子事件的理解。

DESCRIPTION (provided by applicant): BRCA1 is for the cellular to DNA and for reco`mbination, although required response damage homologous it is not yet clear exactly what role it plays in these critical processes. BRCA1 also acts as a co-activator of p53-responsive promoter elements, suggesting that modulating expression of genes that mediate apoptosis and cell cycling is part of this process. Yet, given the universal nature of these cellular processes, it is difficult to explain the striking differences in cancer risk between breast and other tissues in women with BRCA1 germline mutations. The answer will lie in a meticulous dissection of events that initiate and drive BRCAl-associated tumorigenesis. One important clue is that of hormone responsiveness in the tissues at highest risk. During the last funding period, we developed a murine model that recapitulates a known disease-associated human germline BRCA1 mutation with a conditional deletion of the C-terminus of Brca1. We will use that model to ask: What genetic events are necessary for BRCA1-related tumors to develop? The specific aims of this proposal are: Aim 1: To generate murine mammary hyperplasia and carcinomas in mice with a homozygous deletion of the Brcal BRCT domain. Aim 2: To define the early genetic changes in BRCA1 related tumorigenesis using genomic analyses of murine and human tissue Aim3: To define the role of estrogen in the initiation and progression of Brcal-associated mammary tumors. Aim 4: To evaluate the role of haploinsufficiency in BRCA1 mut/wt cells. The completion of this work will define pathways that are altered in BRCAl-associated cancers and will determine whether ER-negative breast cancers predominate in women with BRCA1 mutations because they arise from cells that are intrinsically ER negative or because other proliferative advantages replace ER signaling. We will determine whether heterozygous BRCA1 wt/mut cells have higher mutation rates than BRCA1 wt/wt cells, and whether this effect, if present, is enhanced by estrogen. A complete understanding of these events will lead to testable strategies for prevention, early diagnosis and treatment for women with BRCA1 mutations as well as an enhanced understanding of the molecular events that drive cancer development in general.