Effects of Ethanol Exposure During Involution on Post-Partum Breast Cancer"

描述（由申请人提供）：乳房对致癌的易感性受到暴露于致癌损伤期间乳房微环境发育动态的影响。例如，大鼠在青春期（乳腺快速重塑的“发育窗口期”）暴露于化学致癌物与肿瘤发生增加有关。与性发育期相似，哺乳期后复发最近被认为是乳腺重塑的发育窗口期。虽然胎次通常会对终生乳腺癌风险产生长期保护作用，但最近发现，哺乳期后复归的乳腺重塑是导致产后妇女乳腺癌风险显著增加的原因。这项拨款的前提是，哺乳后复发的短暂窗口期是饮食干预的敏感目标，无论是阳性还是阴性的药物，都是人类乳腺癌风险的明确调节剂。酒精暴露是一种饮食因素，它已被清楚地证明会以剂量依赖的方式增加女性患乳腺癌的风险。然而，在乳腺快速重塑的短时间内，如哺乳期后复复期，乙醇暴露对乳腺癌风险的影响可能是饮食干预的未知目标。本研究的目的是验证乙醇摄入与绝经期暴露窗口之间的协同作用，从而显著增加与生育相关的乳腺癌风险，并通过对乳腺结构和组成的长期影响来实现这一假设。这一假设将在两个特定目标中得到验证，这两个目标都是利用转基因MMTV-Her-2/ new小鼠，这些小鼠在乳腺上皮中过表达野生型Her2受体，并以偶比依赖的方式产生高外显率的乳腺肿瘤。目的1将比较在复归过程中饲喂乙醇14天，在复归第4天、第9天和第21天改变小鼠乳腺组织结构、生化和分子组成的能力。选择这些时间点来比较乙醇在乳腺复归高峰（第4天）、新完成的重构（第9天）和完全建立的哺乳后休息、回归状态（第21天）时对乳腺的影响。目的2将评估同样14天的乙醇喂养方案对该转基因小鼠模型中自发产生的乳腺肿瘤的潜伏期、多样性、生长和转移的影响。肿瘤将被采集，并通过微阵列分析检查乙醇喂养对组织病理学、血管密度、蛋白质靶点的生化表达和基因表达的影响。这些研究结果将为合理设计，以发育为目标的化学预防策略建立新的范式，利用生理性乳腺重塑的特定时间点，开发安全有效的短期饮食干预措施，以预防人类乳腺癌。

DESCRIPTION (provided by applicant): Susceptibility of the breast to carcinogenesis is influenced by the developmentally dynamic state of the mammary microenvironment during the time of exposure to carcinogenic insult. For example, exposure of rats to chemical carcinogens during peripuberty, a "developmental window" of rapid mammary remodeling, is associated with increased tumorigenesis. Similar to peripuberty, post-lactational involution has been recently recognized as a developmental window of mammary gland remodeling. Although parity in general induces a long-term protective effect on life-long breast cancer risk, the mammary gland remodeling of post-lactational involution has recently been identified as contributing to the significantly increased breast cancer risk seen in post-partum women. The premise of this grant is that the brief window of post-lactational involution is a sensitive target for dietary intervention by both positive and negative agents which act as defined modifiers of human breast cancer risk. Ethanol exposure is one dietary factor which has been clearly shown to increase breast cancer risk in women in a dose-dependent fashion. However, the effects of ethanol exposure during brief periods of rapid mammary gland remodeling, such as post-lactational involution, on breast cancer risk may present unrecognized targets for dietary intervention. The purpose of this proposal is to test the hypothesis that ethanol consumption synergistically interacts with the exposure window of involution to substantially increase parity-associated breast cancer risk, and that this occurs through long-lasting effects on mammary gland structure and composition. This hypothesis will be tested in two Specific Aims, both utilizing the transgenic MMTV-Her-2/neu mice, which overexpress wild type Her2 receptors in the mammary epithelium and develop mammary tumors with a high penetrance in a parity-dependent fashion. Aim 1 will compare the ability of ethanol, fed for 14 days throughout involution, to alter the histological structure and biochemical and molecular composition of the mouse mammary gland at day 4, day 9 and day 21 of involution. These time points were chosen to compare ethanol's effects on the mammary gland at times of peak involution (day 4), newly completed remodeling (day 9) and the fully established post-lactational resting, regressed state (day 21). Aim 2 will assess the ability of the same regimen of 14 days of ethanol feeding to influence the latency, multiplicity, growth and metastasis of mammary tumors that arise spontaneously in this transgenic mouse model in a parity-dependent fashion. Tumors will be harvested and examined for effects of ethanol feeding on histopathology, blood vessel density, and biochemical expression of protein targets, and gene expression by microarray analysis. The results of these studies will establish a new paradigm for rationally designed, developmentally-targeted chemopreventive strategies to harness specific time points of physiologic mammary gland remodeling for the development of safe and effective short-term dietary interventions to prevent human breast cancer. PUBLIC HEALTH RELEVANCE: Despite the recent confirmation of ethanol as a risk factor for breast cancer, there is a need for more specific dietary recommendations that address periods of increased susceptibility of the breast of ethanol exposure, rather than total abstention. The purpose of the current research proposal is to test the hypothesis that the time period of post-lactational involution represents a potentially modifiable period of tissue reprogramming, during which time the dietary environment has the potential to enhance the long-term risk of developing parity- associated breast cancer, or alternately, protect against these insults. Using the MMTV-Her-2/Neu transgenic mouse model, in which wild type Her-2/neu is overexpressed in the mammary gland epithelium in a parity- dependent manner, we will examine how ethanol exposure during post-lactational involution alters susceptibility to parity-associated breast cancer.