Insulin-Like Growth Factor I Is Essential for Terminal End Bud Formation and Ductal Morphogenesis during Mammary Development1

Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I(−/−) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1–3) IGF-I administration to IGF-I(−/−) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean of 1.3 in controls to 20.5 without added E2 (P < 0.009), and from 1.7 to 21 when des (1–3) IGF-I was given together with E2 (P < 0.006). The number of ducts increased significantly from a mean of 12 to 27 in response to IGF-I and E2, and from 15 to 24.5 with IGF-I alone. In contrast, administration of human GH with E2 had no stimulatory effect on mammary development in these animals, indicating that the full effect of GH in this process is mediated by IGF-I. To determine whether IGF-I was also responsible for further ductal morphogenesis, we administered des (1–3) IGF-I + E2 to the knockout animals for 14 days and compared the effects of this combination of hormones on mammary development with those observed after 5 days. We found that there was a significant increase from 5 to 14 days in the number of TEBs (mean: 21 vs. 41) and the area of the mammary fat pad occupied by glands (mean: 10 vs. 20%). There was elongation and thickening of the ducts which accounted for the increased area that was occupied by ductal structures. There was no significant increase in the number of ducts. However, there was the appearance of a large number of buds along the length of the ductal structures, suggesting the beginning of side branching. These results suggest that IGF-I, when given along with E2, is responsible for ductal morphogenesis.