RETINOIC ACID INHIBITION OF INSULIN-LIKE GROWTH-FACTOR-I STIMULATION OF C-FOS MESSENGER-RNA LEVELS IN A BREAST-CARCINOMA CELL-LINE

Retinoic acid (RA) inhibits insulin-like growth factor I (IGF-I)-stimulated growth of the human breast carcinoma cell line MCF-7. RA-mediated inhibition of IGF-I-stimulated growth is not associated with either a decrease in IGF-I receptor number or affinity. Since IGF-I modulation of c-fos gene expression appears to be an important step in IGF-I-mediated cellular proliferation, we investigated whether RA inhibits IGF-I stimulation of c-fos mRNA levels. Treatment of MCF-7 cells with IGF-I resulted in an approximately 10-fold increase in c-fos mRNA levels. Pretreatment of MCF-7 cells with 1 mu M RA blocked IGF-I-mediated enhancement of c-fos mRNA levels by approximately 70%. The maximal RA effect (80% inhibition) on IGF-I stimulation of c-fos mRNA levels was noted within 2 h of exposure to RA. IGF-I did not modulate the c-fos gene promoter and appears to increase the stability of the c-fos mRNA. Preexposure of cells to RA results in a significant decrease (P < 0.05) in c-fos mRNA stability. The half-life of c-fos mRNA in the IGF-I-treated cells is 53 +/- 6 min while that in RA-pretreated cells is 27 +/- 0.4 min. We conclude that RA-mediated inhibition of IGF-I stimulation of c-fos mRNA may represent a potential mechanism by which RA inhibits IGF-I stimulation of growth. (C) 1994 Academic Press, Inc.