Epigenetics of Hormone Signaling in Breast Development and Cancer

乳房发育和癌症中激素信号传导的表观遗传学

• 批准号: 8633705
• 负责人: MYLES A BROWN
• 金额: $ 26.57万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633705
• 关键词: Address; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Breast; Breast Cancer Cell; Breast Epithelial Cells; Cell surface; Cells; ChIP-seq; Chemoprevention; Chromatin; Collaborations; Dependence; Development; EZH2 gene; Employee Strikes; Epigenetic Process; Estrogen Receptors; Estrogen receptor positive; Estrogens; Fluorescence-Activated Cell Sorting; Gene Expression; Gene Silencing; Genes; Genetic; Genome engineering; Genomics; Genotype; Hormonal; Hormones; Human; Hyperplasia; Lead; Maintenance; Malignant Neoplasms; Mammary gland; Maps; Mastectomy; Mediating; Mus; Oncogenes; Oncogenic; Pathology; Play; Population; Prevention approach; Prevention therapy; RNA Interference; Receptor Signaling; Relative (related person); Reporting; Role; SET Domain; Signal Transduction; Site; Sorting - Cell Movement; Stem cells; Testing; Validation; Woman; carcinogenesis; castration resistant prostate cancer; histone methyltransferase; histone modification; hormone therapy; malignant breast neoplasm; mammary epithelium; neoplastic cell; new therapeutic target; novel strategies; overexpression; progenitor; programs; prophylactic; receptor binding; transcriptome sequencing; tumor progression

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.

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。我们已经使用细胞表面标记和荧光激活细胞分选的正常乳腺细胞从表面上正常的妇女接受减少乳房成形术，可操作地定义成熟的管腔，管腔祖细胞和基底/乳腺干细胞富集群体。在目标1中，我们将检验乳腺癌中雌激素受体（ER）信号传导重现腔祖细胞中发现的ER信号传导的假设。了解正常管腔祖细胞的ER调节程序对激素化学预防和内分泌治疗具有重要意义。 我们还开始研究BRCA 1和BRCA 2基因型对ER信号传导和正常乳腺表观遗传状态的潜在影响。目的2将测试的假设，BRCA 1和BRCA 2除了其在维持基因组完整性的充分记录的作用发挥重要作用，在决定乳腺细胞的命运和ER信号影响这些效果。 在初步研究中，我们已经发现，由BRCA 2携带者衍生的管腔祖细胞异常表达的基因显示出与我们最近定义为在去势抵抗中表观遗传调节因子EZH 2的致癌功能中发挥重要作用的基因表达程序的惊人重叠。 前列腺癌目的3将阐明EZH 2在正常乳腺发育中起必要作用和在乳腺癌中起致癌作用的假设。 这三个具体目标主要取决于病理学核心和本计划项目支持的合作力量。