Probing the role of epigenomics in Brca1-deficient mammary tumors.

摘要/项目摘要 每年，全世界有50多万妇女死于乳腺癌。巨大的努力已经取得了 对了解原发性疾病和靶向治疗的发展产生影响。然而，这些疗法 许多妇女最初仍然失败，而其他人则复发，患上了耐药疾病。因此，我们必须把重点放在 开发更好的工具来预测高危人群的疾病易感性，同时加强对 以分子为基础的策略来预防乳腺癌。 更具体地说，BRCA 1基因的突变及其随之而来的功能丧失是临床上最常见的 增加个体对乳腺癌易感性的相关基因组改变。不过，并不是所有的女人 BRCA 1基因突变的人会患乳腺癌。因此，我们需要清楚地了解 控制着癌症的易感性我们的主要目标是确定表观基因组如何改变 Brca-1缺陷型乳腺肿瘤。 我们以前证明，乳腺上皮表观基因组和特定的染色质重塑， 这些因素在肿瘤发生进展中起作用。现在，我们假设表观基因组同样 BRCA 1突变乳腺肿瘤的发展。我们将使用乳腺肿瘤发生的创新模型 具体剖析影响Brca 1缺陷型乳腺癌发生的表观遗传机制， 肿瘤的 通过研究特定表观遗传调节因子（BPTF）和全球表观基因组计划的影响， （妊娠）对乳腺肿瘤进展的影响，我们还可以确定预后生物标志物，使我们能够 确定哪些妇女将受益于治疗。最终，我们希望在临床前验证我们的假设 使用正常和恶性的人类乳腺类器官培养物，以帮助制定策略， 作为人类的一级预防。

Abstract/Project Summary Every year, breast cancer kills more than a half-million women worldwide. Monumental efforts have made an impact toward understanding primary disease and the development of targeted therapies. Yet, these therapies still fail many women initially, and others relapse with therapy-resistant disease. Thus, we must focus on developing better tools to predict disease susceptibility in those at higher risk, while augmenting the search for molecularly based strategies to prevent breast cancer. More specifically, mutations in the BRCA1 genes, and their consequent loss of function, are the most clinically relevant genomic alterations that increase the susceptibility of individuals to breast cancer. Still, not all women with BRCA1 mutations will develop breast cancer. Thus, we need a clear picture of the mechanisms that govern cancer susceptibility. Our main goal is to define how the epigenome alters the development of Brca-1 deficient mammary tumors. We previously demonstrated that the mammary epithelium epigenome and specific chromatin remodeling factors play a role in oncogenesis progression. Now, we hypothesize that the epigenome similarly contributes to the development of BRCA1 mutant breast tumors. We will use innovative models of mammary oncogenesis to specifically dissect epigenetic mechanisms that influence the development of Brca1-deficient mammary tumors. By investigating the effects of a specific epigenetic regulator (BPTF) and a global epigenomic program (pregnancy) on mammary tumor progression, we may also identify prognostic biomarkers that will enable us to identify women who will benefit from therapy. Ultimately, we hope to validate our hypotheses pre-clinically using normal and malignant human breast organoid cultures, to aid the development of strategies that will be useful as primary prevention in humans.