Age Dependence of Breast Cancer

乳腺癌的年龄依赖性

• 批准号: 8570537
• 负责人: Michael Y Sherman
• 金额: $ 21.36万
• 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/8570537
• 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风险因素。例如，乳腺癌的发病率随着年龄的增长呈指数级增长，直到绝经期，在这一点上，增长率放缓。对于Her2阳性癌症，在绝经前观察到癌症发病率的整个年龄依赖性增加，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。在这里，基于对人群和动物研究的分析，我们确定可以使用Her2阳性乳腺癌模型在小鼠中研究年龄对肿瘤发展的影响。该试点项目旨在描述Her2阳性癌症发展中的推定年龄依赖性因素。在目标1中，我们将建立一个动物模型，以阐明年龄相关的影响Her2阳性癌症的发展。为此目的，我们将利用转基因小鼠品系，表达Her2在乳腺组织中的调节方式。将在年轻和中年动物中诱导Her2，并将比较乳腺肿瘤出现的时间过程和肿瘤的多样性。使用该模型，我们将直接检验年龄影响乳腺组织对Her2癌基因的反应的假设。在目标2中，我们将讨论肿瘤发展中年龄相关因素的性质的机制问题。这一目的是基于我们的数据，即（1）Her2在人和小鼠乳腺上皮中诱导衰老相关蛋白p21，（2）p21除了衰老外还可以通过控制转录因子SNAIL的表达来调节上皮间质转化（EMT），以及（3）在小鼠模型中，Her2介导的p21上调在中年时减少。后一种效应与炎症途径有关。在这里，我们将测试一个假设，即p21诱导的年龄依赖性下降是促进EMT的重要年龄相关因素，并最终促进肿瘤的出现。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EMT标志物组的表达水平来直接检验这一假设。最后，我们将把表达Her2的小鼠与p21基因敲除的动物杂交，以测试p21对小鼠模型中Her2阳性癌症发展中的年龄依赖性成分的影响。总体而言，该计划将建立一个适当的模型来研究Her2阳性癌症的年龄依赖性，并阐明负责年龄依赖性的分子途径。