TARGETED EXPRESSION OF DES(1-3) HUMAN INSULIN-LIKE GROWTH-FACTOR-I INTRANSGENIC MICE INFLUENCES MAMMARY-GLAND DEVELOPMENT AND IGF-BINDING PROTEIN EXPRESSION

To test the hypothesis that insulin-like growth factor I (IGF-I) regul ates mammary gland development and lactation, the expression of both h uman (h) IGF-I and des(1-3)hIGF-I was targeted to the mammary gland in transgenic mice using a novel exon replacement strategy and the rat w hey acidic protein (rWAP) gene regulatory sequences. Both transgenes e xpressed a 0.7-kilobase messenger RNA (mRNA). The abundance of WAP-IGF -I and WAP-DES mRNA on day 10 of lactation ranged from 0.2-1.0% and 0. 2-13% of the endogenous mouse WAP mRNA, respectively. For WAP-DES mice , transgene expression was greatest from midpregnancy throughout lacta tion. Western blot analysis showed the presence of correctly processed hIGF-I in milk from these transgenic mice. This hIGF-I was capable of stimulating protein synthesis in cultured rat L6 myoblasts. Ligand bl otting indicated changes in mammary gland secretion of IGFBP in respon se to WAP-DES expression. Histological analysis of mammary tissue from mice overexpressing des(1-3)hIGF-I showed incomplete mammary involuti on, ductile hypertrophy, and loss of secretory lobules associated with increased deposition of collagen. These changes are believed to occur through autocrine and paracrine effects of des(1-3)-hIGF-I on both ep ithelial and stromal cells.