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 i s 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.
Generally, cancer is considered to be an age-related disorder, although the molecular nature of age- related effect(s) on breast cancer is not understood. Here, we propose a pilot program to understand aging factors that affect cancer development using models of Her2-positive breast cancer.
|Yaglom, Julia A; McFarland, Christopher; Mirny, Leonid et al. (2014) Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer. Oncotarget 5:8367-78|