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

描述(由申请人提供)：乳房对致癌的敏感性受到乳房微环境在暴露于致癌侮辱期间的发育动态状态的影响。例如，大鼠在青春期期间暴露于化学致癌物，这是乳房快速重塑的“发育窗口”，与肿瘤形成的增加有关。与青春期前相似，哺乳期后退缩最近被认为是乳腺重塑的发育窗口。虽然通常情况下，产次对终身乳腺癌风险有长期的保护作用，但最近发现，哺乳期后退缩的乳腺重塑是导致产后女性乳腺癌风险显著增加的原因之一。这笔赠款的前提是，哺乳期后退缩的短暂窗口是积极和消极因素饮食干预的敏感目标，积极和消极因素都是人类乳腺癌风险的明确修饰者。酒精暴露是一种饮食因素，已被明确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暂时期，如哺乳期后退缩，酒精暴露对乳腺癌风险的影响可能会成为饮食干预的未知靶点。这项建议的目的是检验这样一个假设，即酒精消费与退化暴露窗口协同作用，显著增加与生育相关的乳腺癌风险，并且这是通过对乳腺结构和组成的长期影响而发生的。这一假说将在两个特定的目标上得到验证，这两个目标都是利用转基因MMTV-HER-2/neu小鼠，这些小鼠在乳腺上皮中过度表达野生型Her2受体，并以一种依赖于胎次的方式发展出具有高外显性的乳腺肿瘤。目的1比较乙醇在退化过程中喂养14天，在退化第4天、第9天和第21天改变小鼠乳腺的组织结构和生化及分子组成的能力。选择这些时间点，比较乙醇对乳房退化高峰(第4天)、新完成重塑(第9天)和完全建立的哺乳期后静息、退化状态(第21天)的影响。目的2将评估相同方案的14天酒精喂养的能力，以影响乳腺肿瘤的潜伏期，多样性，生长和转移，在这个转基因小鼠模型中自发产生的胎次依赖的方式。将采集肿瘤，并通过微阵列分析检测乙醇喂养对组织病理学、血管密度、蛋白质靶标的生化表达和基因表达的影响。这些研究的结果将为合理设计、以发展为目标的化学预防策略建立一个新的范例，以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。 与公众健康相关：尽管最近证实酒精是乳腺癌的危险因素，但仍有必要提出更具体的饮食建议，解决乳房对酒精暴露的易感性增加的时期，而不是完全戒酒。目前的研究建议的目的是检验这样一种假设，即哺乳期后退缩的时间段代表着潜在的组织重新编程的可修改时期，在此期间，饮食环境有可能增加患与生育相关的乳腺癌的长期风险，或者替代地，防止这些侮辱。利用MMTV-HER-2/Neu转基因小鼠模型，在该模型中，野生型HER-2/neu以一种与生育有关的方式在乳腺上皮细胞中过表达，我们将研究哺乳后退缩期间的乙醇暴露如何改变与生育相关的乳腺癌的易感性。

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.