Reduced inducibility of SOCS3 by interferon gamma associates with higher resistance of human breast cancer lines as compared to normal mammary epithelial cells
The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the antiproliferative effect of interferon gamma in relation to SOCS3 expression in a panel of breast cancer cell lines and normal mammary epithelial cells. Compared to normal cells most breast cancer lines (7/8) were highly resistant to IFN-gamma. Using Northern blot and real time RT-PCR we investigated transcription of SOCS3 genes. All normal epithelial cells (4/4) showed SOCS3 induction (2-14 fold) while most breast cancer lines did not or weakly activated SOCS3 after the interferon gamma treatment. Among the cancer lines, the MDA-MB-468 cells showed increased sensitivity to IFN-gamma and relatively high level of SOCS3 induction (2-3 fold). Together, there was a good correlation (P < 0.001) between SOCS3 inducibility and growth inhibition by IFN-gamma. The correlations between sensitivity and STAT1 phosphorylation levels (pY-701) were less pronounced since there were cases of STAT1-pY induction (2/12) without apparent growth inhibitory effect. The data indicate defective STAT1 phosphorylation and SOCS3 induction in breast cancer cells. These defects likely contribute to reduced sensitivity of malignant cells to antiproliferative effect of IFN-gamma.