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.

遗传学在进度和激素依赖性对新地址的发展中的详细措施已经开始表观遗传状态。从表面上的正常妇女进行的司法细胞的活化细胞分类，其经历了乳房成形术，定义了成熟的腔内祖细胞。 AIM 1中的富集人群将测试Breat canChancepital的雌激素受体（ER）的信号。 我们还开始研究BRCA2基因型对ER信号传导的潜在影响和AIM 2。命运和ER信号会影响这些影响。 在初步研究中，我们拥有基因异常的生命，我们最近将基因定义为在表观遗传调节剂EZH2中扮演的角色 前列腺癌。 三个特定的目的急剧取决于病理核心核心和该计划项目所支持的合作。