Age Dependence of Breast Cancer

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，乳腺癌发病率随着年龄的增长呈指数增加，直到绝经，在这一点上，增加的速度放缓。对于Her2阳性的癌症，癌症发病率的整个年龄相关性增加是在绝经前观察到的，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合适的动物模型。在这里，基于对人群和动物研究的分析，我们发现可以使用Her2阳性乳腺癌模型在小鼠身上研究年龄对肿瘤发展的相关影响。这个试点项目的目的是描述一个可能的年龄依赖因素(S)在Her2阳性癌症的发生中。在目标1中，我们将建立一个动物模型来阐明与年龄相关的对Her2阳性癌症发生的影响。为此，我们将利用一种在乳腺组织中以受调控的方式表达Her2的转基因小鼠品系。在青年和中年动物中诱导HER2，并比较乳腺肿瘤出现的时程和肿瘤的多样性。利用这个模型，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，我们将解决与年龄相关的因素在肿瘤发展中的本质的机制问题。这一目的是基于我们的数据：(1)Her2在人和小鼠的乳腺上皮中都诱导了衰老相关蛋白p21，(2)除了衰老之外，p21还可以通过控制转录因子蜗牛的表达来调节上皮间充质转化(EMT)，以及(3)在小鼠模型中，Her2介导的p21的上调在中年时减弱。后一种效应与炎症途径有关。在这里，我们将检验一个假设，即p21诱导的年龄相关性下降是促进EMT并最终促进肿瘤出现的一个重要的年龄相关因素。我们将通过比较表达Her2的幼年和中年动物乳腺组织中p21、Snail和一组EMT标记物的表达水平来直接检验这一假设。最后，我们将用表达Her2基因的小鼠与p21基因敲除的动物杂交，以测试p21在小鼠模型中对Her2阳性肿瘤发生过程中年龄相关成分的影响。总体而言，该计划将建立一个适当的模型来研究Her2阳性癌症的年龄相关性，并阐明导致年龄相关性的分子途径。

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.