Involvement of insulin-like growth factors-I and -II and their receptors in medroxyprogesterone acetate-induced growth of mouse mammary adenocarcinomas

The role of the insulin-like growth factors (IGFs) system was investigated in hormone-dependent (HD) and -independent (HI) in vivo lines of the medrox yprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. IGF -II protein and message showed a three- to four-fold increase in HD lines g rowing in MPA-treated mice, as compared with HD tumors growing in untreated mice. Progression to a hormone-independent phenotype in all these lines wa s accompanied by a high constitutive expression of IGF-II. Similar IGF-I mR NA levels were detected in HD and HI lines. Both IGF-I and -II messages aro se from the malignant epithelial cells, as shown by in situ hybridization s tudies. A significant decrease in Man-6P/type II IGF-R content was detected in HD tumors growing in MPA-treated mice as compared with HD lines growing in untreated mice. On the other hand, in HI tumors, notwithstanding high I GF-II synthesis, the levels of Man-6P/type II IGF-R remain high. Competitiv e inhibition and affinity labeling studies showed an almost exclusive bindi ng of IGF-II to Man-6P/type II IGF-R on tumor membranes. The involvement of IGFs in the growth of epithelial primary cultures of the C4-HD line was ev aluated. Exogenous IGF-I potentiated MPA stimulatory effect at concentratio ns of 50-100 ng/ml. Treatment of C4-HD cells with antisense oligodeoxynucle otides (ASODNs) to type I IGF-R and to IGF-II RNA resulted in a dose-depend ent inhibition of MPA-mediated cell proliferation. The inhibition caused by IGF-II ASODNs could not be overcome by the addition of IGF-II up to 150 ng /ml. ASODNs to type I IGF-R at 40 mu g/ml reduced by 75% the number of type I IGF-R; ASODNs to IGF-II at 1 mu M decreased by 83% the levels of IGF-II protein. Our results provide support for the involvement of IGF-I and -II i n MPA-induced mammary tumor growth by autocrine pathways. (C) 1998 Elsevier Science Ltd. All rights reserved.