(Diversity supplement to R01CA188096) Targeting autophagaphy in hereditary breast cancer

 描述（由申请人提供）：遗传性乳腺癌源于“易感性”基因（如BRCA 1、BRCA 2和PALB 2）的遗传突变，这些基因编码在同源重组（HR）介导的DNA双链断裂修复和细胞周期检查点反应中发挥重要作用的大型肿瘤抑制蛋白。此外，这些蛋白质还在氧化应激反应中起作用。由于BRCA/PALB 2蛋白在DNA修复中的作用的开创性发现，现在使用铂类药物和PARP抑制剂靶向缺陷肿瘤细胞的修复缺陷。然而，突变细胞倾向于对这两种类型的药物产生耐药性。因此，为了预防和更好地治疗癌症，必须找到新的途径来选择性地杀死突变细胞，最好是那些靶向不同途径的细胞。使用我们的Palb 2条件性敲除小鼠模型，我们已经确定自噬是乳腺癌发展过程中Palb 2缺陷细胞的保护机制。我们的研究结果表明，在面对DNA损伤和氧化应激引起的PALB 2损失，自噬反对p53介导的障碍，以促进肿瘤发生。基于BRCA 1/2和PALB 2的分子功能和临床表型之间的相似性，我们假设自噬抑制可能阻止PALB 2和BRCA相关遗传性乳腺癌的发生和进展。在这项提案中，我们将使用条件性敲除和诱导性敲除小鼠模型来测试这一假设，并部署体内，体外和体外分析和代谢组学的组合，以确定自噬促进与HR缺乏和氧化应激相关的癌症发展的分子机制。在目标1中，我们将定义自噬在PALB 2和BRCA 1/2缺失后乳腺上皮细胞命运中的作用。在目标2中，我们将定义自噬在Palb 2和Brca 1/2相关乳腺肿瘤发展中的作用，并探索自噬抑制预防和治疗的潜力。在Aim 3中，我们将研究自噬介导的促进Palb 2和Brca 1/2相关乳腺肿瘤发生的机制。

 DESCRIPTION (provided by applicant): Hereditary breast cancers stem from inherited mutations in "susceptibility" genes such as BRCA1, BRCA2 and PALB2, which encode large tumor suppressor proteins that play essential roles in homologous recombination (HR)-mediated DNA double strand break repair and cell cycle checkpoint response. Moreover, these proteins also function in oxidative stress response. As a result of seminal discoveries of the role of the BRCA/PALB2 proteins in DNA repair, the repair defect of the deficient tumor cells is now being targeted using platinum drugs and PARP inhibitors. However, the mutant cells tend to develop resistance to both types of drugs. Thus, for both prevention and better treatment of the cancers, it is imperative to find new avenues to selectively kill the mutant cells, preferably ones that taret different pathways. Using our Palb2 conditional knockout mouse model, we have identified autophagy as a protective mechanism for Palb2-deficient cells during breast cancer development. Our results suggest that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, autophagy opposes a p53-mediated barrier to facilitate tumorigenesis. Based on the similarities between the molecular functions and clinical phenotypes of BRCA1/2 and PALB2, we hypothesize that autophagy inhibition may prevent the development and impede the progression of both PALB2- and BRCA-associated hereditary breast cancers. In this proposal, we will use conditional knockout and inducible knockdown mouse models to test the hypothesis, and deploy a combination of in vivo, ex vivo and in vitro analyses and metabolomics to identify the molecular mechanisms by which autophagy promotes the development of cancers associated with HR deficiency and oxidative stress. In Aim 1, we will define the role of autophagy in mammary epithelial cell fate following PALB2 and BRCA1/2 loss. In Aim 2, we will define the role of autophagy in Palb2- and Brca1/2- associated mammary tumor development and explore the potential of autophagy inhibition for prevention and treatment. In Aim3, we will investigate the mechanisms of autophagy-mediated promotion of Palb2- and Brca1/2-associated mammary tumorigenesis.