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

摘要/项目摘要 每年，全世界有50多万女性死于乳腺癌。不朽的努力取得了 对了解原发疾病和开发靶向治疗的影响。然而，这些疗法 许多女性最初仍然失败，其他人又复发了，患有抗药性疾病。因此，我们必须重点关注 开发更好的工具来预测高危人群的疾病易感性，同时扩大对 预防乳腺癌的基于分子的策略。 更具体地说，BRCA1基因的突变及其导致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，并不是所有的女性 BRCA1基因突变会发展成乳腺癌。因此，我们需要对这些机制有一个清晰的了解 控制癌症易感性。我们的主要目标是定义表观基因组如何改变 BRCA-1缺陷型乳腺肿瘤。 我们先前证明了乳腺上皮表基因组和特异的染色质重塑 这些因素在肿瘤的发生发展中起着重要作用。现在，我们假设表观基因组也有类似的贡献 BRCA1突变型乳腺肿瘤的发生。我们将使用创新的乳腺肿瘤发生模型 具体剖析影响BRCA1缺陷乳腺发育的表观遗传学机制 肿瘤。 通过研究特定的表观遗传调节因子(BPTF)和全球表观基因组计划的影响 (怀孕)在乳腺肿瘤进展方面，我们还可以识别预后生物标记物，使我们能够 确定哪些女性将从治疗中受益。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器官培养，以帮助制定将被 在人类中作为一级预防有用。

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.