INVOLUTION OF THE LACTATING MAMMARY-GLAND IS INHIBITED BY THE IGF SYSTEM IN A TRANSGENIC MOUSE MODEL

Development of the mammary gland during puberty, pregnancy, and lactat ion is controlled by steroid and peptide hormones and growth factors. To determine the role of the insulin-like growth factors (IGFs) in thi s process we developed a transgenic model using the whey acidic protei n (WAP) gene to direct expression of rat IGF-I and human IGF binding p rotein-3 (IGFBP-3) to mammary tissue during late pregnancy and through out lactation. High levels of expression of transgenic IGF-I and IGFBP -3 were seen in lobular-alveolar cells by in situ hybridization. There was no obvious effect on mammary development during pregnancy and lac tation; indeed, mothers were capable of nursing their, pups normally a nd the only structural difference seen in the mammary glands at peak l actation was an overall smaller size of the alveoli. We also evaluated the role of IGF-I and IGFBP-3 in the remodeling of mammary tissue dur ing involution, Compared with control animals, the process of involuti on was modified in both transgenic lines, The degree of apoptotic cell s was lower in the WAP-IGF-I and WAP-BP-3 expressing mice. In addition , there was a more quiescent pattern of involution with residual lobul ar secretory ability and a muted host inflammatory reaction with fewer lumenal microcalcifications. These results demonstrate that IGF-I and IGFBP-3 may modulate the involutionary process of the lactating mamma ry gland.