HORMONAL-REGULATION OF INSULIN-LIKE GROWTH-FACTOR-II AND INSULIN-LIKEGROWTH-FACTOR BINDING-PROTEIN EXPRESSION BY BREAST-CANCER CELLS IN-VIVO - EVIDENCE FOR STROMAL EPITHELIAL INTERACTIONS

Insulin-like growth factors (IGFs) I and II are potent mitogens for br east cancer cells. Their proliferative activity is likely to be influe nced by their binding proteins (IGFBPs), a family of newly identified proteins. We report here on the in vivo hormonal regulation of mRNAs f or IGF-II and IGFBPs in the N-nitrosomethylurea-induced rat mammary tu mor, a well-established model of hormone-responsive mammary cancer. IG F-II mRNA levels tended to decrease in regressing tumors following ova riectomy, and they markedly increased upon reactivation of tumor growt h with hormone repletion. Ovariectomy induced a drastic increase in IG FBP-6 mRNA which was reversible with hormone repletion. Similar but mo re modest changes were observed with IGFBP-2 mRNA. In contrast, IGFBP- 3 and IGFBP-4 mRNAs tended to decrease with ovariectomy and increase w ith hormone repletion. These latter effects, however, mere modest, var iable, and not statistically significant. In situ hybridization analys is revealed that IGF-II, IGFBP-5, and IGFBP-6 mRNAs were localized in the stromal component of the tumor, whereas IGFBP-2 mRNA was expressed by epithelial cells. We conclude that hormonal regulation of IGFBP ex pression is heterogeneous, thus suggesting divergent biological functi ons for these peptides. Our data also emphasize the importance of pote ntial stromal-epithelial interactions in the control of breast cancer cell proliferation by IGFs.