title: Notch-induced mammary tumorigenesis does not involve the lobule-limited epithelial progenitor.
abstract: The mouse mammary epithelial cell hierarchy contains both multipotent stem cell as well as lineage-limited duct and lobular progenitor cell functions. The latter-also termed parity-identified mammary epithelial cells (PI-MECs)-are marked by beta-galactosidase (β Gal) expression following pregnancy and involution in whey acidic protein promoter (WAP)-Cre/Rosa26-flox-stop-flox-lacZ (WC/R26) mice, and are the targets of tumorigenic transformation in mouse mammary tumor virus-erbB2 transgenic mice. In this study, we demonstrate that an epithelial population distinct from PI-MECs is transformed during WAP-Int3 tumorigenesis. As expected, WAP-Int3/WC/R26 triple-transgenic mice failed to undergo secretory alveolar development, failed to lactate and developed mammary tumors. Following pregnancy and involution, β Gal+ mammary epithelial cells were found in the normal mammary tissue, but the resulting mammary tumors were all β Gal-. WAP-Int3/WC/R26 mammary glands contained ample estrogen receptor alpha (ERα)+ MECs, but only rare (<1%) progesterone receptor (PR)+ and RANKL+ cells. In addition, dissociated MECs from WAP-Int3/WC/R26 glands failed to regenerate a mammary tree upon transplantation into a cleared fat-pad of a nu/nu recipient mouse. However, when mixed with normal MECs, PI-MECs from WAP-Int3/WC/R26 mice contributed progeny to the resulting functional outgrowth. The WAP-Int3/WC/R26-derived PI-MECs displayed all of the properties of fully functional lobular progenitors including giving rise to ERα+, PR+, smooth muscle actin+ and RANKL+ epithelial progeny. These results demonstrate that WAP-Int3 has no oncogenic effect upon PI-MECs and that the expansion of functional lobular progenitors is required for secretory alveolar development and lactation. Furthermore, lobular progenitor function is ultimately controlled by signals within its microenvironment.
authors.affiliation: Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Bruno
authors.forename: C A
authors.initials: CA
authors.lastname: Boulanger
authors.forename: G H
authors.initials: GH
authors.lastname: Smith
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*
chemical_list: D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C024471:whey acidic proteins; C073572:Notch4 protein, mouse