Involvement of insulin-like growth factors-I and -II and their receptors in medroxyprogesterone acetate-induced growth of mouse mammary adenocarcinomas (original) (raw)
1998, The Journal of Steroid Biochemistry and Molecular Biology
The role of the insulin-like growth factors (IGFs) system was investigated in ho,:iiione-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balblc mice. IGF-II protein and message showed a three-to four-fold increase in HD lines growing in MPA-treated mice, as compared with HD tumors growing in untreated mice. Progression to a hormone-independent phenotype in all these lines was accompanied by a high constitutive expression of IGF-II. Similar IGF-I mRNA levels were detected in HD and HI lines. Both IGF-I and -II messages arose from the malignant epithelial ceils, as shown by in situ hybridization studies. 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 IGF-II synthesis, the levels of Man-6Pltype II IGF-R remain high. Competitive inhibition and affinity labeling studies showed an almost exclusive hinding of IGF-II to Man-6PItype II IGF-R on tumor membranes. The involvement of IGFs in the growth of epithelial primary cultures of the C4-HD line was evaluated. Exogenous IGF-I potentiated MPA stimulatory effect at concentrations of 50-100 nglml. Treatment of C4-HD ceils with antisense oligodeoxynucleotides (ASODNs) to type I IGF-R and to IGF-II RNA resulted in a dose-dependent 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 nglml. ASODNs to type I IGF-R at 40 pglml reduced by 75% the number of type I IGF-R; ASODNs to IGF-II at 1 decreased by 83% the levels of IGF-II protein. Our results provide support for the involvement of IGF-I and -II in MI'A-induced mammary tumor growth by autocrine pathways.
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