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，每八名妇女中就有一名患有乳腺癌。 在她生命中的某个时刻患上了癌症[1]。一些乳腺癌风险因素与乳腺癌组织重塑有关。 妊娠和哺乳[2]。其中包括，第一次足月妊娠时年龄较大（>35岁）， 妊娠（未产）和从未哺乳（哺乳）[3，4]。妊娠期乳腺组织发育 泌乳是由孕激素受体和催乳素受体的作用介导的，此外， 激素[5，6]。此外，表观遗传调节是在组织重建过程中发生的组织重建的可能驱动因素。 怀孕[7]。 本研究将调查怀孕期间乳房的表观遗传重塑，特别关注 孕激素和催乳素的活性。此外，它还将寻求分析出 两种孕酮亚型PRA和PRB在产次/哺乳和癌症之间的关系。PRA 和PRB，它们被认为协同作用以调节PR相关基因表达[8，9]。畸变率 在乳腺肿瘤中发现了50%的同种型组成[9]，但尚未记录到比例的变化 在正常的怀孕过程中。因此，了解孕激素受体生物学在 怀孕期间正常乳房重塑的背景对产次和乳房重塑之间的关系很重要。 癌症风险。通过整合关于产次诱导的表观遗传变化的信息， 孕酮受体和催乳素受体（或催乳素下游的转录因子）的两种亚型 受体），更好地了解胎次和哺乳改变乳房的分子基础 癌症的风险将得到实现。 本项目旨在阐明孕激素受体和催乳素受体作为激素驱动因子的作用， 产次和哺乳期的表观遗传重编程，重点是表观基因组作为一种生物学机制 将早期怀孕与预防乳腺癌发展的晚年保护联系起来。研究目的 为： 目的1：描述妊娠期间和妊娠后妊娠诱导的乳腺上皮细胞染色质修饰 和哺乳期。 目的2：鉴定孕激素受体和孕激素受体激动剂对染色质结构和基因表达的影响， 催乳素受体活性，使用体外细胞培养模型。 目的3：研究孕酮的表观遗传和转录反应中同工型生物学的作用 受体在体外细胞培养模型中。