Environmental Effect on the Mammary Gland across the Lifespan

描述(申请人提供)：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。暴露在环境因素中会对乳腺发育产生影响，并可能影响乳腺癌的风险。这个项目探索了在整个生命周期中易感窗口的潜在机制。通过定义整个生命周期内乳腺发育和变化的分子结构，研究人员将能够开发新的和改进的动物模型和生物标记物，以研究环境应激源对乳腺癌的影响，阐明在正常和易患肿瘤的动物的关键脆弱窗口期间暴露时间的影响。该项目将使用最先进的成像、蛋白质组和遗传学工具来确定环境侮辱何时、哪些以及如何调节小鼠乳腺在体内发育过程中的细胞行为，以及乳腺上皮细胞向癌前表型的转化。实验将合作进行，使用器官类型培养和小鼠模型来表征与早期生命、青春期、怀孕和其他时间点的乳房发育相关的途径，并确定它们如何受到发生在不同脆弱窗口的环境应激源的影响。在小鼠身上的这些研究将补充使用培养中的人乳房上皮来开发新的分析方法，以评估外源性物质如何改变它们克服有限寿命和细胞间相互作用施加的限制的能力。通过定义易感性的关键窗口，以及创建将导致识别生物标记物的改进的动物和人类细胞培养模型，这些研究有可能转化为女性，以确定环境应激源对乳腺癌的影响。研究人员建议确定在活体小鼠乳腺微环境和乳腺上皮细胞在生命周期中的力学性质的变化。研究人员将确定在生命周期中暴露于典型环境应激源对体内正常和易患癌症的小鼠以及人类乳房标本的乳腺的影响。他们将使用基于体外机制的分析来检测具有可能的乳腺致癌性特征的试剂。该项目将通过信息交流、互动和协作参与BCERP网络活动。这项建议的一个基本特点是与社区倡导团体定期进行双向沟通，以侧重于适当的环境应激源，开发生物标记物，并将调查结果转化为一般术语。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. Exposures to environmental agents can have an effect on mammary gland development and may affect breast cancer risk. This project explores the mechanisms underlying windows of susceptibility during across the lifespan. By defining the molecular architecture of the developing and changing mammary gland over the lifespan the investigators will be able to develop new and improved animal models and biomarkers to study the Impact of environmental stressors on breast cancer, elucidate the effects of timing of exposure during critical windows of vulnerability in both normal and tumor prone animals. This project will use state-of-the-art imaging, proteomic and genetic tools to determining when, which and how environmental insults regulate cell behavior in the mouse mammary gland during development in vivo, and in conversion of mammary epithelial cells to premalignant phenotypes. Experiments will be conducted cooperatively, using organotypic cultures and mouse models to characterize pathways related to breast development during early life, puberty, pregnancy, and other time points, and to determine how they are affected by exposures to environmental stressors occurring at different windows of vulnerability. These studies in mice will be complemented using human breast epithelium in culture to develop new assays that can assess how exogenous agents alter their ability to overcome finite lifespan and constraints imposed by intercellular interactions. By defining critical windows of vulnerability, and creating improved animal and human cell culture models that will lead to identification of biomarkers, these studies have the potential for translation to women to determine the impact of environmental stressors on breast cancer. The investigators propose to determine the alterations in the mechanical properties of mammary microenvironment in mice in vivo and the mammary epithelial cells during the life cycle. The investigators will determine the effects of exposure to prototypical environmental stressors during the life cycle on the mammary gland in normal and cancer prone mice in vivo and in human breast specimens. They will use in vitro mechanism-based assays to detect agents that possess signatures indicative of possible mammary gland carcinogenicity. This project will participate in the BCERP Network activities by exchange of information, interactions and collaborations. An essential feature of this proposal is regular bidirectional communication with the community-based advocacy group to focus on appropriate environmental stressors and to develop biomarkers and to translate the findings into lay terms.