ECTOPIC TGF-BETA-1 EXPRESSION IN THE SECRETORY MAMMARY EPITHELIUM INDUCES EARLY SENESCENCE OF THE EPITHELIAL STEM-CELL POPULATION

An important feature of the mammary gland is the regenerative capacity of its epithelium which is demonstrated upon successive cycles of lac tation and involution. Pregnant mice expressing a whey-acidic protein (WAP) promoter-driven transforming growth factor-beta 1 (TGF beta 1) c DNA are unable either to generate a secretory mammary epithelium or to lactate. Here we investigate whether ectopic TGF beta 1 induces this phenotype by affecting the transgenic epithelium directly or in trans. Reciprocal transplantation of mammary tissue between normal and trans genic hosts resulted in the development of the respective phenotypes o f the transplants within the same mammary fat pad. When isolated mamma ry epithelial cells from both were mixed before implantation so that t ransgenic and normal epithelium would develop together more proximatel y, both phenotypes were simultaneously observed in the resultant chime ric mammary outgrowths. Since no trans effect was detectable, we hypot hesize that early expression of the transgene results in compromised l obular progenitor cells through an intracrine mechanism. Consistent wi th this posit, WAP promoter-driven protein expression was detected in individual cells of the subtending ducts of immature females at estrus . Transplantation of WAP-TGF beta 1 mammary gland into nonpregnant hos ts revealed that transgenic implants, even those from young postpubert al virgin females, had a diminished ability to repopulate epithelium-f ree mammary fat pads. Accordingly, the ectopic expression of WAP-TGF b eta 1 not only impairs lobular progenitors, but also promotes an early senescence of the regenerative capacity of the mammary ductal epithel ium. This leads us to propose that mammary epithelial stem cells give rise to two functionally distinct progenitor cells in the mammary glan d epithelium: one capable of producing daughters committed to ductal f ormation, the other capable only of producing daughters committed to l obular function. (C) 1995 Academic Press, Inc.