REVERSION TO THE NONTRANSFORMED PHENOTYPE OF TSSV40-TRANSFORMED UTERINE ENDOMETRIAL EPITHELIAL-CELLS IS ACCOMPANIED BY DECREASED MITOGENIC RESPONSIVENESS TO IGFS AND BY ENHANCED SECRETION OF AT LEAST 5 DIFFERENT IGF BINDING-PROTEINS

The insulin-like growth factors (IGFs-I and -II), the IGF binding prot eins (IGFBPs) and the IGF receptors may constitute a complex regulator y network underlying normal and neoplastic growth of uterine epitheliu m. This study examined the mitogenic effects of the IGFs as well as th e production of IGFBPs by the HRE-H9 (H9) endometrial epithelial cell line, previously isolated from pseudopregnant rabbit uterus using temp erature-sensitive (ts)SV40 (Li et al., 1989). Transformed (33 degrees C and 37 degrees C) but not nontransformed (40 degrees C) H9 cells exh ibited mitogenic responses to exogenous IGFs. Characterization of micr osomal membranes from transformed cells identified IGF-I and -II recep tors and membrane-associated IGFBP(s). Total protein and IGFBP content of H9 conditioned medium (CM) at different incubation temperatures va ried (40>37>33 degrees C) and CM from cells at 40 degrees C was the mo st inhibitory to basal and IGF-I stimulated mitogenesis of H9 cells. T ransformed and nontransformed H9 cells synthesized IGFBPs-2, -3, -4, - 5 and -6 mRNAs and proteins. Results implicate at least five different IGFBPs in the differential response of transformed vs. nontransformed H9 cells to exogenous IGFs. Moreover, reduced levels of IGFBPs in the extracellular environment may contribute to the increased proliferati ve capacity of SV40-transformed endometrial epithelial cells.