Environmental Effect on the Mammary Gland across the Lifespan

描述（由申请人提供）：乳腺癌是妇女癌症死亡的第二大原因，也是妇女中最常见的癌症。暴露于环境因素会对乳腺发育产生影响，并可能影响乳腺癌的风险。该项目探讨了整个生命周期中易感性窗口的潜在机制。通过定义乳腺在整个生命周期中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志物来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易感性窗口期间暴露时间的影响。该项目将使用最先进的成像、蛋白质组学和遗传学工具来确定环境损伤在小鼠乳腺体内发育过程中何时、以何种方式以及如何调节细胞行为，以及如何调节乳腺上皮细胞向癌前表型的转化。实验将进行合作，使用器官型培养和小鼠模型来表征生命早期、青春期、怀孕和其他时间点与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性窗口的环境压力源的影响。这些小鼠研究将在人类乳腺上皮的培养中进行补充，以开发新的检测方法，以评估外源性药物如何改变其克服有限寿命和细胞间相互作用所施加的限制的能力。通过定义关键的脆弱性窗口，并创建改进的动物和人类细胞培养模型，将导致识别生物标志物，这些研究有可能转化为女性，以确定环境压力源对乳腺癌的影响。研究人员拟确定小鼠体内乳腺微环境的力学特性和乳腺上皮细胞在生命周期中的变化。研究人员将确定在生命周期中暴露于典型环境应激源对正常和易患癌症的小鼠乳腺的影响，以及对人类乳腺标本的影响。他们将使用基于体外机制的检测方法来检测具有可能的乳腺致癌性特征的药物。该项目将通过交换信息、相互作用和协作参与BCERP网络活动。该提案的一个基本特征是与社区倡导团体定期进行双向沟通，以关注适当的环境压力因素，开发生物标志物，并将研究结果转化为专业术语。

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.