title: Reducing mammary cancer risk through premature stem cell senescence.
abstract: The reproductive capacity of the mammary epithelial stem cell is reduced coincident with the number of symmetric divisions it must perform. In a study of FVB/N mice with the transgene, WAP-TGFbeta1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-beta1. To test whether premature aging of mammary epithelial stem cells would have an impact on susceptibility or resistance to mammary cancer, female littermates from FVB/N x WAP-TGF-beta1 mating were injected with mouse mammary tumor virus (MMTV) at 8-10 weeks of age. A total of 44 females were inoculated, maintained as breeders and observed for tumor development for 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 epithelial cells in infected glands were identified by transplantation of single cell (1 x 10(5)) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-beta1 cells, both MMTV-infected TGF-beta1 and wild type cells produced hyperplastic outgrowths suggesting that premalignant transformation was achieved in each group. The results suggest a positive correlation between the procreative life-span of mammary epithelial stem cells and mammary cancer risk.
authors.affiliation: Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, MD 20892, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Boulanger
authors.forename: G H
authors.initials: GH
authors.lastname: Smith
mesh_terms: D000818:Animals; D002472:Cell Transformation, Viral; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology / Q000821:virology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D012192:Retroviridae Infections / Q000473:pathology; D013234:Stem Cells / Q000166:cytology* / Q000821:virology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014412:Tumor Virus Infections / Q000473:pathology; D016662:Virus Integration
chemical_list: D008894:Milk Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C024471:whey acidic proteins