Abstract
BackgroundSuppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer.MethodsWe determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry.ResultsSOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002).ConclusionThis is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors.
Highlights
Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as signal transducer and activator of transcription (STAT) induced inhibitors of the Jak/Stat pathway
To evaluate the potential significance of SOCS expression in mammary carcinoma for prognosis and its association with clinicopathological characteristics we have investigated the mRNA levels of SOCS1, SOCS2, SOCS3 and cytokine-inducible SH2 containing protein (CIS) in a representative collection of primary breast cancers specimens
SOCS and insulin-like growth factor 1 (IGF-I) mRNA and clinicopathological features The mRNA content of SOCS1, SOCS2 and IGF-I was assessed in 89 primary breast cancer samples, and of SOCS3 and CIS in 64 samples
Summary
Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. SOCS proteins comprise a family of eight members (SOCS1-7 and CIS), which have initially been described as STAT induced STAT inhibitors or more generally as negative regulators of cytokine signaling via the Jak/Stat pathway. Their ability to modulate signal transduction is based on two functional domains, an SH2 domain, which binds to phosphorylated tyrosine residues and a SOCS box, which serves as a recruiting site for ubiquitin ligases [1]. Whereas epidemiological data indicate that high levels of circulating serum IGF-I are associated with an increased risk for the development of solid tumors including breast cancer, little is known on the role of autocrine produced IGF-I [15,17]. High IGF-I mRNA levels were associated with good prognosis, suggesting that secretion of IGF-I by the tumor is a property of a less malignant and more differentiated tumor
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