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 medroxyprogesterone 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 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 cells, 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-6P/type II IGF-R remain high. Competitive inhibition and affinity labeling studies showed an almost exclusive binding 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 evaluated. Exogenous IGF-I potentiated MPA stimulatory effect at concentrations of 50-100 ng/ml. Treatment of C4-HD cells 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 ng/ml. ASODNs to type I IGF-R at 40 microg/ml reduced by 75% the number of type I IGF-R; ASODNs to IGF-II at 1 microM decreased by 83% the levels of IGF-II protein. Our results provide support for the involvement of IGF-I and -II in MPA-induced mammary tumor growth by autocrine pathways.
Elizalde
P V
PV
Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina. elizalde@proteus.dna.uba.ar
Lanari
C
C
Molinolo
A A
AA
Guerra
F K
FK
Balañá
M E
ME
Simian
M
M
Iribarren
A M
AM
Charreau
E H
EH
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005260:Female; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D017527:Receptor, IGF Type 2 / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D017527:Receptor, IGF Type 2; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017258:Medroxyprogesterone Acetate; D017526:Receptor, IGF Type 1