Epigenetics of Hormone Signaling in Breast Development and Cancer

详细了解遗传学和表观遗传学在不同乳腺癌亚型的进展和激素依赖性中的相互作用，对于开发新的预防和治疗方法至关重要。为了解决这个问题，我们已经开始探索正常乳腺上皮细胞和肿瘤细胞的表观遗传状态。我们使用细胞表面标记物和荧光激活的细胞分选技术，从表面上看正常的乳房缩小术患者的乳腺细胞中，确定成熟的管腔、管腔祖细胞和基础/乳腺干细胞的富集群。在目标1中，我们将检验这一假设，即乳腺癌中的雌激素受体(ER)信号重现了在腔前体细胞中发现的ER信号。了解正常腔前体细胞的内质网调节程序对激素化学预防和内分泌治疗都有重要意义。 我们还开始研究BRCA1和BRCA2基因对ER信号和正常乳腺的表观遗传状态的潜在影响。目的2将验证这一假设，即BRCA1和BRCA2除了在维持基因组完整性方面的已知作用外，还在决定乳腺细胞命运中发挥重要作用，并且ER信号影响这些作用。 在初步研究中，我们发现BRCA2携带者的腔祖细胞异常表达的基因与我们最近定义的在抗去势的表观遗传调控因子EZH2的致癌功能中发挥重要作用的基因表达程序有显着重叠 前列腺癌。目标3将阐述EZH2在正常的乳腺发育和乳腺癌的致癌作用中发挥必要作用的假设。 这三个具体目标在很大程度上取决于病理学核心和本计划项目所支持的合作的力度。

A detailed understanding of interplay between genetics and epigenetics in the progression and hormone dependence of distinct breast cancer subtypes is critical to the development of new approaches to prevention and therapy. To address this problem we have begun to explore the epigenetic state of the normal mammary epithelial cells and of tumor cells. We have used cell surface markers and fluorescence¿ activated cell sorting of normal mammary cells from ostensibly normal women undergoing reduction mammoplasty to operationally define mature luminal, luminal progenitor and basal/mammary stem cell¿ enriched populations. In Aim 1 we will test the hypothesis that estrogen receptor (ER) signaling in breast cancer recapitulates ER signaling found in luminal progenitors. An understanding of the ER-regulated program in normal luminal progenitors has important implications for both hormonal chemoprevention and for endocrine therapy. We have also begun to investigate the potential impact of BRCA1 and BRCA2 genotype on ER signaling and the epigenetic state of the normal mammary gland. Aim 2 will test the hypothesis that BRCA1 and BRCA2 in addition to their well-documented roles in maintaining genomic integrity play important roles in determining mammary cell fate and that ER signaling influences these effects. In preliminary studies we have found that the genes aberrantly expressed by luminal progenitor cells derived from BRCA2 carriers shows a striking overlap with the gene expression program that we recently defined as playing an important role in the oncogenic function of the epigenetic regulator EZH2 in castration-resistant prostate cancer. Aim 3 will address the hypothesis that EZH2 plays a necessary role' in normal mammary development and an oncogenic role in breast cancer. These three specific aims depend critically on the Pathology Core and the strength of the collaborations supported by this Program Project.