TARGETING EXPRESSION OF A TRANSFORMING GROWTH-FACTOR-BETA-1 TRANSGENETO THE PREGNANT MAMMARY-GLAND INHIBITS ALVEOLAR DEVELOPMENT AND LACTATION

Transforming growth factor-beta1 (TGF-beta1) possesses highly potent, diverse and often opposing cell-specific activities, and has been impl icated in the regulation of a variety of physiologic and developmental processes. To determine the effects of in vivo overexpression of TGF- beta1 on mammary gland function, transgenic mice were generated harbor ing a fusion gene consisting of the porcine TGF-beta1 cDNA placed unde r the control of regulatory elements of the pregnancy-responsive mouse whey-acidic protein (WAP) gene. Females from two of four transgenic l ines were unable to lactate due to inhibition of the formation of lobu loalveolar structures and suppression of production of endogenous milk protein. In contrast, ductal development of the mammary glands was no t overtly impaired. There was a complete concordance in transgenic mic e between manifestation of the lactation-deficient phenotype and expre ssion of RNA from the WAP/TGF-beta1 transgene, which was present at lo w levels in the virgin gland, but was greatly induced at mid-pregnancy . TGF-beta1 was localized to numerous alveoli and to the periductal ex tracellular matrix in the mammary gland of transgenic females late in pregnancy by immunohistochemical analysis. Glands reconstituted from c ultured transgenic mammary epithelial cells duplicated the inhibition of lobuloalveolar development observed in situ in the mammary glands o f pregnant transgenic mice. Results from this transgenic model strongl y support the hypothesis that TGF-beta1 plays an important in vivo rol e in regulating the development and function of the mammary gland.