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.

对遗传学与表观遗传学之间的相互作用的详细理解在不同乳腺癌亚型的进展和马匹依赖性方面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。我们已经使用了细胞表面标记和荧光。从表面上正常乳腺成形术的正常妇女的正常乳腺细胞的激活细胞分选中，以操作定义成熟的腔腔，腔内祖细胞和碱性/乳腺干细胞。在AIM 1中，我们将检验以下假设：乳腺癌中雌激素受体（ER）信号传导概括了腔祖细胞中发现的ER信号传导。对正常腔内祖细胞中的ER调节程序的理解对马匹化学预防和内分泌治疗都具有重要意义。 我们还开始研究BRCA1和BRCA2基因型对ER信号传导和正常乳腺的表观遗传状态的潜在影响。 AIM 2将检验以下假设：BRCA1和BRCA2除了证明其在维持基因组完整性方面的作用外，在确定乳细胞命运方面起着重要作用，并且ER信号传导影响了这些效果。 在初步研究中，我们发现，源自BRCA2载体的腔祖细胞异常表达的基因表明，我们最近将其定义为在表观遗传调节剂EZH2的致癌功能中起重要作用，这与基因表达程序重叠，在castratiation抗性抗性中起着重要作用。 前列腺癌。 AIM 3将解决以下假设：EZH2在正常的乳腺发育中起必要的作用，并且在乳腺癌中起致癌作用。 这三个特定的目标在很大程度上取决于该计划项目支持的病理核心和协作的实力。