Age Dependence of Breast Cancer

乳腺癌的年龄依赖性

• 批准号: 8668909
• 负责人: Michael Y Sherman
• 金额: $ 17.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668909
• 关键词: Address; Affect; Age; Age Factors; Aging; Animal Model; Animals; Data; Dependence; Development; Disease; Doxycycline; Epithelial; Epithelium; Human; Incidence; Individual; Inflammatory; Investigation; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Menopause; Mesenchymal; Modeling; Molecular; Mouse Mammary Tumor Virus; Mouse Strains; Mus; Nature; Oncogenes; Pathway interactions; Pilot Projects; Play; Risk Factors; Role; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Up-Regulation; age effect; age related; animal population study; base; cancer type; knockout animal; malignant breast neoplasm; mammary epithelium; mouse model; oncoprotein p21; programs; public health relevance; response; senescence; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Aging is a risk factor in development of certain types of cancer. For example, breast cancer incidence increases with ageing exponentially until menopause, at which point the rate of increase slows down. With Her2-positive cancer, the entire age-dependent increase in cancer incidence is observed before menopause, i.e. in mid-age individuals. An important problem which hampers investigation of effects of aging on cancer is the lack of adequate animal models. Here, based on analyses of both population and animal studies we identify that age-related effects on tumor development can be investigated in mice using models of Her2- positive breast cancer. This pilot project is aimed to delineate a putative age-dependent factor(s) in development of Her2-positive cancer. In Aim 1, we will establish an animal model to elucidate age-related effects on development of Her2-positive cancer. For this purpose, we will utilize a transgenic mouse strain that expresses Her2 in mammary tissue in a regulated manner. Her2 will be induced in young and mid-age animals and time-course of the mammary tumor emergence and the multiplicity of tumors will be compared. Using this model, we will directly test the hypothesis that age affects the response of mammary tissue to Her2 oncogene. In Aim 2, we will address the mechanistic question about the nature of the age-related factor in tumor development. This Aim is based on our data that (1) Her2 induces the senescence-associated protein p21 both in human and mouse mammary epithelium, (2) p21 in addition to senescence can regulate epithelium mesenchymal transition (EMT) via controlling expression of the transcription factor SNAIL, and (3) in the mouse model Her2-mediated upregulation of p21 diminishes at mid-age. The latter effect was linked to inflammatory pathways. Here, we will test a hypothesis that age-dependent decline in p21 induction is an important age-related factor that promotes EMT, and eventually facilitates tumor emergence. We will directly test this hypothesis by comparing expression levels of p21, SNAIL, and the set of EMT markers in mammary tissue of Her2-expressing young and mid-age animals. Finally, we will cross Her2-expressing mice with p21 knockout animals to test the impact of p21 on the age-dependent component in development of Her2-positive cancer in the mouse model. Overall this program will both establish an adequate model to study age-dependence of Her2-positive cancer, and clarify the molecular pathway responsible for the age-dependence.

描述（由申请人提供）：衰老是某些类型癌症发展的危险因素。例如，随着年龄的增长，乳腺癌的发病率呈指数增长，直到更年期，这时增长速度减慢。对于her2阳性癌症，在绝经前观察到癌症发病率的完全年龄依赖性增加，即在中年个体中。阻碍研究衰老对癌症影响的一个重要问题是缺乏足够的动物模型。在此，基于对人群和动物研究的分析，我们确定年龄对肿瘤发展的影响可以在使用Her2阳性乳腺癌模型的小鼠中进行研究。该试点项目旨在描述her2阳性癌症发展中一个假定的年龄依赖因素。在目的1中，我们将建立一个动物模型来阐明年龄对her2阳性癌症发展的影响。为此，我们将利用一种转基因小鼠品系，在乳腺组织中以受调节的方式表达Her2。将在中青年动物中诱导Her2，比较乳腺肿瘤出现的时间进程和肿瘤的多样性。使用这个模型，我们将直接检验年龄影响乳腺组织对Her2癌基因反应的假设。在目标2中，我们将解决有关肿瘤发展中年龄相关因素性质的机制问题。本研究基于我们的数据：(1)Her2在人和小鼠乳腺上皮中诱导衰老相关蛋白p21， (2) p21除衰老外，还可以通过控制转录因子SNAIL的表达来调节上皮间充质转化（EMT），(3)在小鼠模型中，Her2介导的p21上调在中年时减弱。后一种效应与炎症途径有关。在这里，我们将验证一个假设，即p21诱导的年龄依赖性下降是促进EMT并最终促进肿瘤出现的重要年龄相关因素。我们将通过比较表达her2的年轻和中年动物乳腺组织中p21、SNAIL和一组EMT标记物的表达水平，直接验证这一假设。最后，我们将把表达her2的小鼠与p21基因敲除动物杂交，在小鼠模型中测试p21对her2阳性癌症发展中年龄依赖性成分的影响。总的来说，本项目将建立一个足够的模型来研究her2阳性癌症的年龄依赖性，并阐明其年龄依赖性的分子途径。