EXPRESSION OF OVINE INSULIN-LIKE GROWTH-FACTOR-I (IGF-1) STIMULATES ALVEOLAR BUD DEVELOPMENT IN MAMMARY-GLANDS OF TRANSGENIC MICE

To determine whether murine mammary growth is modulated by local insul in-like growth factor-1 (IGF-1) production, expression of recombinant IGF-1 was directed to the mammary glands of transgenic mice using an o vine prepro IGF-1 cDNA under control of the mouse mammary tumor virus- long terminal repeat (MMTV-LTR) promoter. Bioactivity of recombinant I GF-1 in transgenic mouse milk extracts was demonstrated by a concentra tion-dependent increase in [H-3]thymidine incorporation in clonal bovi ne mammary epithelial cells (MAC-T) compared with control mouse milk e xtracts; moreover, addition of excess recombinant human insulin-like g rowth factor binding protein-3 (rhIGFBP-3) abolished the increase in [ H-3]thymidine incorporation attributed to recombinant IGF-1 in transge nic mouse milk. Recombinant IGF-1 was produced in mammary tissue of vi rgin and pregnant transgenic mice, and secreted into milk of lactating mice. However, recombinant IGF-1 was not detected in serum from trans genic mice; and ligand blot analysis of serum insulin-like growth fact or binding proteins (IGFBPs) indicated no differences owing to transge ne presence, In peripubertal virgin mice at 49 d of age, the frequency of appearance of mammary alveolar buds was significantly higher in MM TV-IGF-1 than in CD-1 mice, and was unaffected by ovariectomy or estra diol treatment. In conclusion, mammary synthesis of recombinant IGF-1 enhances the rate of development of alveolar buds in mammary glands of virgin transgenic mice.