Pregnancy-induced epigenetic changes in breast duct epithelia as biological mechanism influencing breast cancer risk

妊娠引起的乳腺导管上皮表观遗传变化作为影响乳腺癌风险的生物学机制

• 批准号: 9791608
• 负责人: Elizabeth Marie Martin
• 金额: --
• 依托单位: U.S. NATIONAL INST OF ENVIRON HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791608
• 关键词: ATAC-seq; Age; Age at First Live Birth; Binding; Biochemical; Biological; Biological Assay; Biology; Breast; Breast Cancer Risk Factor; Breast Feeding; CRISPR/Cas technology; Cell Culture Techniques; Cell Line; Cells; ChIP-seq; Chromatin; Chromatin Structure; Complex; Data; Data Analyses; Development; Discipline of Nursing; Disease; Ductal Epithelium; Elderly; Environmental Risk Factor; Epidemiology; Epigenetic Process; Estrogens; Event; Flow Cytometry; Gene Expression; Genetic Transcription; Goals; Heritability; Hormonal; Hormone Receptor; Hormones; Human; In Vitro; Lactation; Life; Life Experience; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Mediation; Mentorship; Mitotic; Modeling; Molecular; Molecular Biology; Mus; Nulliparity; Pattern; Phase; Pregnancy; Process; Progesterone; Progesterone Receptors; Prolactin; Prolactin Receptor; Protein Isoforms; Public Health; Receptor Gene; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; System; T47D; Techniques; Tissues; Training; United States; Woman; chromatin modification; epigenetic regulation; epigenome; in vitro activity; insight; interest; malignant breast neoplasm; mammary epithelium; mouse model; multidisciplinary; parity; pregnant; programs; receptor binding; reproductive; response; transcription factor; transcriptome; transcriptome sequencing

Project Summary Breast cancer is a major public health problem with one in eight women in the United States developing breast cancer at some point within her life [1]. Some breast cancer risk factors are related to tissue remodeling during pregnancy and nursing [2]. They include, late age (>35 years) at first full term pregnancy, never becoming pregnant (nulliparity), and never breastfeeding (lactation) [3, 4]. Breast tissue development during pregnancy and lactation is mediated by the actions of progesterone receptor and prolactin receptor, in addition to other hormones [5, 6]. In addition, epigenetic regulation is a likely driver of tissue remodeling that occurs during pregnancy [7]. This study will investigate epigenetic remodeling in the breast during pregnancy with specific interest in the activity of the key pregnancy hormones, progesterone and prolactin. In addition, it will seek to parse out the roles of the two progesterone isoforms, PRA and PRB, in the relationship between parity/lactation and cancer. PRA and PRB which are thought to act in concert to regulate PR-associated gene expression [8, 9]. Aberrant ratios of the isoform composition are found in breast tumors [9], but changes in the ratios have not been documented in the context of the normal process of pregnancy. Thus, understanding progesterone receptor biology in the context of normal breast remodeling during pregnancy is important to the relationship between parity and breast cancer risk. By integrating information about parity induced epigenetic changes with binding events mediated by both isoforms of progesterone receptor and prolactin receptor (or transcription factors downstream of prolactin receptor), a greater understanding of the molecular underpinnings by which parity and lactation alter breast cancer risk will be achieved. This project seeks to elucidate the role of progesterone receptor and prolactin receptor as hormonal drivers of epigenetic reprogramming during parity and lactation, with a focus on the epigenome as a biological mechanism linking early life pregnancy with later life protection against breast cancer development. The aims of the study are: Aim 1: Describe pregnancy induced chromatin modifications to breast epithelium during and after pregnancy and lactation in a mouse model. Aim 2: Identify chromatin structure and gene expression changes in response to progesterone receptor and prolactin receptor activity using an in vitro cell culture model. Aim 3: Characterize the role of isoform biology in the epigenetic and transcriptional response of progesterone receptor in an in vitro cell culture model.

项目摘要 乳腺癌是一个主要的公共卫生问题，在美国八分之一的妇女发展 她一生中的某个时刻[1]。一些乳腺癌的危险因素与组织重塑有关 怀孕和护理[2]。其中包括第一个全年怀孕的晚期（> 35岁），从不变成 怀孕（无效），从不母乳喂养（哺乳）[3，4]。怀孕期间的乳房组织发育 泌乳是由孕酮受体和催乳素受体的作用介导的，此外 激素[5，6]。此外，表观遗传调节可能是组织重塑的驱动力 怀孕[7]。 这项研究将在怀孕期间研究乳房中的表观遗传重塑，并对 关键妊娠激素，孕激素和催乳素的活性。此外，它将寻求解析角色 在平等/哺乳和癌症之间的关系中，两个孕酮同工型PRA和PRB中的中等。 PRA 和PRB共同作用于调节PR相关的基因表达[8，9]。异常比率 在乳腺肿瘤中发现了同工型组成[9]，但尚未记录比率的变化 在正常的怀孕过程中。因此，了解孕酮受体生物学 怀孕期间正常乳房重塑的背景对于平等与乳房之间的关系很重要 癌症风险。通过整合有关奇偶校验引起的表观遗传变化与结合事件介导的结合事件的信息 孕酮受体和催乳素受体的两种同工型（催乳素下游的转录因子 受体），对均等和泌乳改变乳房的分子基础有更深入的了解 将实现癌症风险。 该项目旨在阐明孕酮受体和催乳素受体作为激素驱动因素的作用 在平等和哺乳期间的表观遗传重编程，重点是表观基因组作为生物学机制 将早期妊娠与以后的生命保护联系起来，以防止乳腺癌发育。研究的目的 是： 目的1：描述怀孕期间和妊娠后乳腺上皮的染色质修饰 和鼠标模型中的泌乳。 AIM 2：确定染色质结构和基因表达对孕酮受体的响应变化， 使用体外细胞培养模型的催乳素受体活性。 AIM 3：表征同工型生物学在孕酮表观遗传和转录反应中的作用 体外细胞培养模型中的受体。