Expression of STAT1 target genes and interferon gamma in human mammary carcinoma tissue

Background

The signal transducer and activator of transcription 1 (STAT1) in human primary mammary carcinoma was found to be a predictor of good prognosis for the outcome of disease [1]. This is in accordance with its documented role in growth arrest and in pro-apoptotic signaling.

Methods

In order to define signaling pathways employed by STAT1 to exert its effect on the tumor and to define the role of interferon gamma (IFN-γ) in its activation, we have investigated the expression of known STAT1 target genes and of IFN-γ in the primary tumor by quantitative RT-PCR. The study was performed with a total of 111 different primary tumor samples.

Results

The expression of the two tumor suppressor genes IRF-1 and suppressor of cytokine signaling 1 (SOCS1) were found to be correlated with the activation status of STAT1, as determined by measuring tyrosine phosphorylation of STAT1 by western blotting, DNA binding by electromobility shift assays and nuclear localization by immunohistochemistry. IFN-γ expression was correlated to the expression of some, but not all, STAT1 target genes. However, it did not correlate with constitutive STAT1 activation. Survival analysis revealed that, in contrast to STAT1 activation, IFN-γ expression was not a predictor of a longer overall or relapse-free survival.

Conclusions

Our results indicate that, in the majority of primary mammary carcinomas investigated, the constitutive activation of STAT1 does not depend on increased IFN-γ secretion (e.g. as a result of an inflammatory reaction in the tumor). This suggests a prominent role for IFN-γ-independent mechanisms leading to the constitutive activation of STAT1 in primary mammary carcinomas. The frequent induction of the tumor suppressor genes SOCS1 and IRF-1 in carcinoma tissue with activated STAT1 implies a potential role of these genes in mediating the good prognostic effects of STAT1 activation.