Primate mammary gland insulin-like growth factor system: Cellular localization and regulation by sex steroids

Background: Insulin-like growth factor 1 (IGF1) plays a critical role in es trogen-induced uterine proliferation, but it is unclear whether this estrom edin function occurs in other estrogen-sensitive tissues such as the mammar y gland, To elucidate this possibility, we investigated the cellular locali zation and hormonal regulation of mRNAs for IGF1 and 2, their cognate recep tors (IGF1R, IGF2R), and IGF binding proteins 2-5 (BPs 2-5) in the rhesus m onkey mammary gland. Methods: Ovariectomized monkeys were treated with placebo, estradiol (E2), and E2 plus progesterone (E2/P4) for 3 days, after which mammary tissue was harvested for in situ hybridization and immunohistochemical analyses. Results: IGF1 and IGF2 mRNA levels were significantly increased and BP2 mRN A decreased by E2 and by E2/P4 treatment, IGF1R mRNA was increased by combi ned E2/P treatment but not by E2 alone. BP5 mRNA was decreased by E2/P4, No differences in IGF2R, BP3, and BP4 mRNA levels were detected in any treatm ent group, Mammary IGF1 and IGF2 mRNA levels were both positively correlate d with local epithelial proliferation, assessed by immunodetection of the p roliferation-specific antigen, Ki67, IGF1 and IGF1R expression were negativ ely correlated with local programmed cell death, as assessed by the in situ TUNEL method, In contrast, BP2 expression was negatively correlated with e pithelial proliferation and positively correlated with programmed cell deat h, IGF2R, BP3, BP4, and BP5 levels were not significantly correlated with e ither proliferation or death. Conclusions: Thus, E2-induced proliferation is associated with upregulation of both IGF1 and IGF2 expression and downregulation of BP2 expression, The se data suggest that the local mammary IGF system is involved in sex steroi d-induced mammary epithelial cell hyperplasia.