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

项目摘要 乳腺癌是一个主要的公共健康问题，美国每八名女性中就有一人患有乳房 在她生命中的某个时刻患上癌症[1]。一些乳腺癌危险因素与组织重塑有关 怀孕和哺乳[2]。包括，高龄(35岁)在第一次足月怀孕时，永远不会 怀孕(未分娩)，从未哺乳(哺乳)[3，4]。孕期乳房组织发育 而哺乳是由孕激素受体和催乳素受体的作用以及其他 激素[5，6]。此外，表观遗传调控可能是组织重塑的一个驱动因素 怀孕[7]。 这项研究将调查怀孕期间乳房的表观遗传重塑，特别是对 孕酮和催乳素这两种关键妊娠激素的活性。此外，它还将寻求分析角色 孕酮的两种亚型，即PRA和PRB，在产次/哺乳与癌症的关系中起重要作用。PRA 和pRb，它们被认为协同作用来调节PR相关基因的表达[8，9]。畸变率 在乳腺肿瘤中发现了多种亚型组成[9]，但这些比例的变化尚未被记录在案。 在正常怀孕过程的背景下。因此，了解孕激素受体生物学在 孕期正常乳房重塑的背景对产次和乳房的关系很重要 癌症风险。通过将有关产次诱导的表观遗传变化的信息与由 孕酮受体和催乳素受体(或催乳素下游转录因子)的两种异构体 受体)，更好地理解产次和哺乳改变乳房的分子基础 癌症风险将会实现。 该项目试图阐明孕激素受体和催乳素受体作为激素驱动因素的作用。 产次和哺乳期间的表观遗传重编程，重点是表观基因组作为一种生物学机制 将早孕与晚年预防乳腺癌的生活保护联系起来。这项研究的目的 包括： 目的1：描述怀孕期间和怀孕后由妊娠引起的对乳腺上皮的染色质修饰 在小鼠模型中进行哺乳。 目的2：确定孕激素受体和孕激素受体对染色质结构和基因表达的影响。 用体外细胞培养模型研究催乳素受体活性。 目的3：研究异构体生物学在孕酮的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。

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.