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

Abstract

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 IFNc, IGF-1 and ionizing radiation, in a normal human mammary epithelial cell line (AG11134), two breastcancer 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 IFNc and/or ionizing-radiation while SOCS3 is transiently down-regulated by IFNc and IGF-1, suggesting that SOCS genes are not silenced in these cells by the epigenetic mechanism of DNAhypermethylation. We further show that the kinetics of SOCS1-mediated feedback inhibition of IFNc 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.

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease

“…43 SOCS5 has been shown to be decreased in prostate cancer cell lines compared to a non-malignant prostate cell line. 44 Collectively, these data support the notion that elevation of hsa-miR-141 and hsa-miR-375 in prostate tumors alters gene expression programs, and that identification of their target genes could yield information regarding prostate cancer biology. We are currently undertaking functional studies to investigate whether these miRNAs contribute to disease development and/or progression.…”

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

“…Indeed, reports describing SOCS-3 hypermethylation and subsequent loss of expression in a variety of cancers support the idea that SOCS-3 may have a tumor-suppressing function (94)(95)(96)(97). In contrast, elevated SOCS-3 expression was reported in human breast cancer and melanoma tissues, as well as in a subset of classic Hodgkin's lymphoma cell lines and primary lymphoma cells (98)(99)(100)(101)(102)(103)(104). In several studies, SOCS-3 promoted cell growth and proliferation in a number of cancers (100,103,105), and elevated levels of SOCS-3 were reported to confer a growth advantage to a melanoma cell line (103).…”

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

“…Interestingly, a good correlation between constitutive SOCS 3 expression, lack of its inducibility and IFN cell resistance was obtained in additional melanoma cell lines (Table 1). The strong upregulation of SOCS 3 following IFN-g could be a specific feature of melanoma lineages because epithelial breast cancer cells showed its downregulation (Evans et al, 2007) or variable expression (Souckova, unpublished data). However, in breast cancer cells SOCS 1 was strongly activated while its induction was rather weak in melanoma lines used.…”

“…In support, three IFN-insensitive WM 1158R, WM 9 and 1205 Lu melanoma lines had high basal expression of SOCS 3 compared to sensitive cells. Furthermore, breast cancer (Evans et al, 2007) and leukaemia cells (Sakai et al, 2002) showed elevated constitutive expression of SOCS 1 and SOCS 3 and the resistance to proinflammatory cytokines including IFN-g. Perhaps IFN sensitivity of a SOCS 3 promoter is reduced due to aberrant expression of an activatory transcription factor(s). In this context, aberrant activation of tissue-specific promoters has been observed in cancers (Kovarik et al, 1993).…”

“…These studies indicated that aberrant silencing could be a cause for constitutive activation of JAK/STAT pathway in cancer cells. However, other studies also indicated that malignant cells compared to their normal counterparts express SOCS genes constitutively (Sakai et al, 2002;Li et al, 2004;Evans et al, 2007) and forced expression of SOCS transgene often conferred resistance to IFN. Constitutive expression can potentially hamper immunotherapy by inactivating cytokine signals.…”