Reducing mammary cancer risk through premature stem cell senescence

The reproductive capacity of the mammary epithelial stem cell is reduced co incident with the number of symmetric divisions it must perform. In a study of FVB/ N mice with the transgene, WAP-TGF beta1, we discovered that mamma ry epithelial stem tells were prematurely aged due to ectopic expression of TGF-beta1. To test whether premature aging of mammary epithelial stem cell s would have an impart on susceptibility or resistance to mammary cancer, f emale littermates from FVB/ N x WAP-TGF-beta1 mating were injected with mou se mammary tumor virus (MMTV) at 8-10 weeks of age. A total of 44 females w ere inoculated, maintained as breeders and observed for tumor development f or up to 18 months. Only one mammary tumor appeared in 17 TGF-beta1 females while 15 were collected from 29 wild type sisters. Premalignant mammary ep ithelial cells in infected glands were identified by transplantation of sin gle cell(1 x 10(5)) suspensions into nulliparous hosts and testing for hype rplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-beta1 cells, both MMTV-infected TGF-beta1 and wild type c ells produced hyperplastic outgrowths suggesting that premalignant transfor mation was achieved in each group. The results suggest a positive correlati on between the procreative life-span of mammary epithelial stem cells and m ammary cancer risk.