In conjunction with our studies on mammary tumorigenesis in feral and inbred mice, our efforts have focused upon understanding the cellular basis of malignant progression in the mammary gland. Taking the point of view that mammary carcinomas arise as clonal populations of transformed tissue-specific stem cells and their differentiating progeny, we have initiated a long-term project aimed at elucidating the cellular, molecular, and genetic events underlying mammary epithelial cell growth, regeneration, and functional development. 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-TGFb1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-b1. 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-b1 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-b1 females while 15 were collected from 29 wild type sisters. Premalignant mammary epithelial cells in infected glands were identified by transplantation of single cell (1x105) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-b1 cells, both MMTV-infected TGF-b1 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.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Booth, Brian W; Boulanger, Corinne A; Smith, Gilbert H (2007) Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation. J Cell Physiol 212:729-36
Boulanger, Corinne A; Mack, David L; Booth, Brian W et al. (2007) Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo. Proc Natl Acad Sci U S A 104:3871-6
Mack, David L; Boulanger, Corinne A; Callahan, Robert et al. (2007) Expression of truncated Int6/eIF3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis. Breast Cancer Res 9:R42
Booth, Brian W; Jhappan, Chamelli; Merlino, Glenn et al. (2007) TGFbeta1 and TGFalpha contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium. Int J Cancer 120:493-9
Wagner, Kay-Uwe; Smith, Gilbert H (2005) Pregnancy and stem cell behavior. J Mammary Gland Biol Neoplasia 10:25-36
Clarke, Robert B; Smith, Gilbert H (2005) Stem cells and tissue homeostasis in mammary glands. J Mammary Gland Biol Neoplasia 10:1-3
Boulanger, Corinne A; Wagner, Kay-Uwe; Smith, Gilbert H (2005) Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 24:552-60
Lowther, William; Wiley, Korah; Smith, Gilbert H et al. (2005) A new common integration site, Int7, for the mouse mammary tumor virus in mouse mammary tumors identifies a gene whose product has furin-like and thrombospondin-like sequences. J Virol 79:10093-6
Smith, Gilbert H (2005) Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 132:681-7
Triplett, Aleata A; Sakamoto, Kazuhito; Matulka, Laurice A et al. (2005) Expression of the whey acidic protein (Wap) is necessary for adequate nourishment of the offspring but not functional differentiation of mammary epithelial cells. Genesis 43:1-11

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