Suppressor of cytokine signaling (SOCS) proteins have emerged as critical attenuators of cytokine-mediated processes, suggesting a role in the suppression of tumorigenesis. In the ovary and mammary gland, cytokines such as prolactin and IL-6 are important regulators of growth and differentiation. We have investigated whether silencing or inactivation of SOCS genes occurs in ovarian and breast carcinomas. The SOCS1 and SOCS2 CpG islands were found to be hypermethylated in 23 and 14% of primary ovarian cancers, respectively, whereas only SOCS1 was methylated in breast cancers (9%). Methylation of these genes did not occur in normal tissues. No correlation was apparent between methylation and loss of heterozygosity, and no somatic mutations were found in a large panel of carcinomas. Aberrant methylation of these SOCS genes correlated with transcriptional silencing in ovarian and breast cancer cell lines, since expression was induced by the demethylating agent 5-azadeoxycytidine. SOCS3 was not hypermethylated in either cancer type. Consistent with this data, SOCS1 and SOCS2 but not SOCS3 suppressed the growth of ovarian and breast cancer cells. Hypermethylation and silencing of specific SOCS genes in the ovary, and to a lesser extent in breast, may augment cytokine responsiveness in these tissues, thereby contributing to oncogenesis.

Differential hypermethylation of SOCS genes in ovarian and breast carcinomas

Protein kinase signaling pathways, such as Janus kinase 2-Signal transducer and activator of transcription 5A/B (JAK2-STAT5A/B), are of significant interest in the search for new therapeutic strategies in both breast and prostate cancers. In prostate cancer, the components of the JAK2-STAT5A/B signaling pathway provide molecular targets for small-molecule inhibition of survival and growth signals of the cells. At the same time, new evidence suggests that the STAT5A/B signaling pathway is involved in the transition of organ-confined prostate cancer to hormone-refractory disease. This implies that the active JAK2-STAT5A/B signaling pathway potentially provides the means for pharmacological intervention of clinical prostate cancer progression. In addition, active STAT5A/B may serve as a prognostic marker for identification of those primary prostate cancers that are likely to progress to aggressive disease. In breast cancer, the role of STAT5A/B is more complex. STAT5A/B may have a dual role in the regulation of malignant mammary epithelium. Data accumulated from mouse models of breast cancer suggest that in early stages of breast cancer STAT5A/B may promote malignant transformation and enhance growth of the tumor. This is in contrast to established breast cancer, where STAT5A/B may mediate the critical cues for maintaining the differentiation of mammary epithelium. In addition, present data suggest that activation of STAT5A/B in breast cancer predicts favorable clinical outcome. The dual nature of STAT5A/B action in breast cancer makes the therapeutic use of STAT5 A/B more complex.

/pdf/signal-transducer-and-activator-of-transcription-5a-b-in-39vorx1ttl.pdf

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

DNA-hypermethylation of SOCS genes in breast, ovarian, squamous cell and hepatocellular carcinoma has led to speculation that silencing of SOCS1 and SOCS3 genes might promote oncogenic transformation of epithelial tissues. To examine whether transcriptional silencing of SOCS genes is a common feature of human carcinoma, we have investigated regulation of SOCS genes expression by IFNgamma, IGF-1 and ionizing radiation, in a normal human mammary epithelial cell line (AG11134), two breast-cancer cell lines (MCF-7, HCC1937) and three prostate cancer cell lines. Compared to normal breast cells, we observe a high level constitutive expression of SOCS2, SOCS3, SOCS5, SOCS6, SOCS7, CIS and/or SOCS1 genes in the human cancer cells. In MCF-7 and HCC1937 breast-cancer cells, transcription of SOCS1 is dramatically up-regulated by IFNgamma and/or ionizing-radiation while SOCS3 is transiently down-regulated by IFNgamma and IGF-1, suggesting that SOCS genes are not silenced in these cells by the epigenetic mechanism of DNA-hypermethylation. We further show that the kinetics of SOCS1-mediated feedback inhibition of IFNgamma signaling is comparable to normal breast cells, indicating that the SOCS1 protein in breast-cancer cells is functional. We provide direct evidence that STAT3 pathways are constitutively activated in MCF-7 and HCC1937 cells and may drive the aberrant persistent activation of SOCS genes in breast-cancer cells. Our data therefore suggest that elevated expression of SOCS genes is a specific lesion of breast-cancer cells that may confer resistance to proinflammatory cytokines and trophic factors, by shutting down STAT1/STAT5 signaling that mediate essential functions in the mammary gland.

Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals.

SOCS1, a prototype molecule of the SOCS family, was initially defined as a suppressor of cytokine signaling. The molecular mechanisms of SOCS1-mediated functions have been subsequently identified by studies using gene knockout mice and gene silencing technology. As part of a negative feedback regulation, SOCS1 downregulates cytokine signaling through direct inhibition of the JAK tyrosine kinase and the signaling cascade of activated cytokine receptors, thereby attenuating cytokine-initiated signal transduction. Moreover, other studies have demonstrated that SOCS1 also downregulates TLR signaling through direct and indirect mechanisms. Both cytokine receptor and TLR signaling pathways mediate important functions in survival, maturation and differentiation of various types of cells and in the regulation of immune function. Abnormal expression of SOCS1 in tumor cells has been detected in various human cancers, where it is associated with dysregulation of cytokine receptor and TLR signaling to promote cell transformation. Recent studies on the function of SOCS1 in tumor cells have revealed its novel role in carcinogenesis. In this review, we will focus on the mechanism of action of SOCS1 in both tumor cells and antigen-presenting cells in the tumor microenvironment. The potential of using SOCS1 as a diagnostic marker and therapeutic target in tumor diagnosis, prognosis and treatment is discussed.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.27318

Role of SOCS1 in tumor progression and therapeutic application.

https://www.jidonline.org/article/S0022-202X(15)32005-4/pdf

Expression of SOCS-1, Suppressor of Cytokine Signalling-1, in Human Melanoma

Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

/pdf/suppressor-of-cytokine-signalling-gene-expression-is-1slrhx4gtu.pdf

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma

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Suppressor of cytokine signalling gene expression is elevated in breast carcinoma