Relationship Between Expression Of Signal Transducer And Activators Of Transcription 3 (STAT3) And Suppressor Of Cytokine Signaling 3 (SOCS3) Protein And Biological Behaviors In Breast Carcinoma

Backgroud:Signal transducers and activators of transcription 3(STAT3) pathway can be activated by cytokines and growth factors,and activation of STAT3 is involved in modulating cell proliferation,differentiation and apoptosis.STAT3 has been classified as an oncogene because STAT3 can mediate malignant transformation of cultured cells.Many studies show that there was obvious difference of STAT3 expression between the poor differentiated breast carcinoma and the well differentiated breast carcinoma. The expression of STAT3 was higher in axillary lymph node metastatic cancers than in non-axillary lymph node metastatic cancers. No obvious difference of STAT3 may contribute to malignant transformation of breast carcinoma.Suppressor of cytokine signaling ( SOCS ) is a new family of immuno-suppressor, including CIS,SOCS1-SOCS7,WSB,ASB,SSB and so on. The functions of SOCS have been revealed more and more since its discovery in 1995, such as negatively regulating signaling by IFN-γ, participating T cell differentiation during the embryonic stage of development and so on. Suppressors of cytokine signaling (SOCS) proteins have emerged as critical regulators of cytokine-mediated signaling in diverse tissues. These proteins act in a negative feedback loop to attenuate signaling via the Janus kinase-Signal transducers and activators of transcription (JAK/STAT) pathway. Recent data have revealed that SOCS genes were frequently aberrantly methylated in a wide variety of human tumors tissue,suggesting the SOCS proteins play a critical role in production, progression, metastasis of the tumor. SOCS3 is one of the most active member of SOCS family. Previous studies indicated that frequent dense hypermethylation of the functional SOCS-3 promoter region was correlated with silencing of the SOCS-3 gene in many cancer samples and cancer cell lines. The data reveals that NSCLC cell lines where SOCS-3 was silenced had higher levels of STAT3 phosphorylation. In contrast, the normal cells that expressed SOCS-3 showed little or no phosphorylation of STAT3. SOCS-3 silencing as a result of promoter methylation may be an important cause of constitutive activation of the JAK/STAT pathway in human tumors. The finding of SOCS-3 silencing by promoter methylation reveals an important epigenetic event during the development of tumor. SOCS-3 is normally activated by JAK/STAT signaling in normal cells, which in turn inhibits JAK activity and subsequent STAT3 activation. Therefore, the phenomenon of SOCS-3 silencing as a result of promoter methylation may be a common event during oncogenesis. SOCS-3 itself may function as an important tumor suppressor gene.In the present study, we sought to determine whether SOCS3 expression is related to the expression of STAT3 and pSTAT3 in breast cancer specimens and whether the expression is correlated with clinical pathological parameters.Objective:To investigate the expression of signal transducer and activators of transcription 3(STAT3) and suppressor of cytokine signaling 3(SOCS3) protein in the breast carcinoma tissue and their relationship with tumor differentiation,invasion and metastasis.Methods:Tissue microarray and immunohistochemistry by EnVision methods were employeed to study 71 archival breast carcinoma samples and 41 noncancerous tissue samples . The presence of STAT3 ,Phospho-STAT3 and SOCS3 protein were investigated in relation to clinical pathological parameters.Results:(1) The positive rates of STAT3,Phospho-STAT3 were significantly higher in breast cancer tissue group than in noncancerous tissue group(78.9% vs.36.6% and 69.0% vs.29.3%,P <0.01),and the positive rate of SOCS3 was significantly higher in noncancerous tissue group than in breast cancer tissue group( 48.8% vs.29.6%, P<0.05 ) ; (2) The expression of STAT3,Phospho-STAT3 was positively related to histological grade,axillary lymph node metastasis and clinica1 stage( P<0.01 ),but was not statistically correlated with age,tumor size and histological type in breast carcinoma tissues(P>0.05). The expression of SOCS3 was negatively related to histopathologic grade,axillary lymph node metastasis ( P<0.05 ),but was not statistically correlated with age,histological type,tumor size and clinical stage(P>0.05).(3) The expression of STAT3,Phospho-STAT3 was negatively related to the expression of SOCS3 in breast carcinoma tissues( P<0.01 ).Conclusions:The overexpression of STAT3, Phospho-STAT3 and the deleted expression of SOCS3 are closely correlated with the tumor carcinogenesis , development , invasion and metastasis of breast carcinoma.Detecting these indexes can be helpful in assessment of the malignancy grade and biological behaviors of breast carcinoma.