Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, MD 20892, USA

Correspondence to: G H Smith, Bldg 10, Room 8B07, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892-1750, USA

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-TGF1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-1. 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´WAP-TGF-1 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-1 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´10⁵) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-1 cells, both MMTV-infected TGF-1 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. Oncogene (2001) 20, 2264-2272.

mammary; stem cell; cancer risk; cellular senescence; MMTV