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

描述（由申请方提供）：乳腺对致癌作用的易感性受到暴露于致癌物损伤期间乳腺微环境发育动态状态的影响。例如，大鼠在青春期前后（快速乳腺重塑的“发育窗口”）接触化学致癌物与肿瘤发生增加有关。与青春期相似，哺乳后退化最近被认为是乳腺重塑的发育窗口。虽然产次一般会对终身乳腺癌风险产生长期保护作用，但最近已确定哺乳后退化的乳腺重塑是导致产后妇女乳腺癌风险显著增加的原因。这项资助的前提是，哺乳后退化的短暂窗口是作为人类乳腺癌风险的定义修饰剂的阳性和阴性药物的饮食干预的敏感目标。乙醇暴露是一个饮食因素，已明确表明，以剂量依赖的方式增加妇女患乳腺癌的风险。然而，在短暂的快速乳腺重塑，如哺乳后退化，对乳腺癌风险的乙醇暴露的影响，可能会提出未被认识的目标，饮食干预。本提案的目的是检验以下假设：乙醇消费与退化暴露窗口协同作用，大幅增加产次相关乳腺癌风险，并且这是通过对乳腺结构和组成的长期影响而发生的。该假设将在两个特定目的中进行检验，均使用转基因MMTV-Her-2/neu小鼠，其在乳腺上皮中过表达野生型Her 2受体，并以胎次依赖性方式发生高转移率的乳腺肿瘤。目的1将比较在整个退化过程中饲喂14天的乙醇在退化第4天、第9天和第21天改变小鼠乳腺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在退化峰值（第4天）、新完成重塑（第9天）和完全建立的哺乳后静息、退化状态（第21天）时对乳腺的影响。目的2将评估相同的14天乙醇喂养方案以胎次依赖性方式影响该转基因小鼠模型中自发出现的乳腺肿瘤的潜伏期、多样性、生长和转移的能力。将收获肿瘤并通过微阵列分析检查乙醇喂养对组织病理学、血管密度和蛋白质靶点的生化表达以及基因表达的影响。这些研究的结果将建立一个新的模式，合理设计，发展有针对性的化学预防策略，利用特定的时间点的生理乳腺重塑的发展安全和有效的短期饮食干预，以预防人类乳腺癌。 公共卫生相关性：尽管最近证实乙醇是乳腺癌的一个危险因素，但仍需要更具体的饮食建议，以解决乳腺对乙醇暴露的敏感性增加的时期，而不是完全避免。当前研究提案的目的是检验以下假设：哺乳后退化的时间段代表了组织重编程的潜在可修改时期，在此期间，饮食环境有可能增加发生产次相关乳腺癌的长期风险，或者保护免受这些伤害。使用MMTV-Her-2/Neu转基因小鼠模型，其中野生型Her-2/neu以胎次依赖性方式在乳腺上皮中过表达，我们将研究哺乳后退化期间的乙醇暴露如何改变对胎次相关乳腺癌的易感性。

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.