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Expression of SOCS1 and SOCS3 Genes Is Differentially Regulated in Breast Cancer Cells in Response to Proinflammatory Cytokine and Growth Factor Signals

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Expression of SOCS1 and SOCS3 Genes Is Differentially Regulated in Breast Cancer Cells in Response to Proinflammatory Cytokine and Growth Factor Signals Oncogene (2007) 26, 1941–1948 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals MK Evans1, C-R Yu2, A Lohani1, RM Mahdi2, X Liu2, AR Trzeciak1 and CE Egwuagu2 1Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA and 2Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA DNA-hypermethylation of SOCS genes in breast, ova- Keywords: breast-cancer cells; SOCS; breast cancer; STAT; rian, squamous cell and hepatocellular carcinoma has led BRCA1; DNA hypermethylation; interferon 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 Introduction IFNc, IGF-1 and ionizing radiation, in a normal human mammary epithelial cell line (AG11134), two breast- Development of the mammary gland is regulated by cancer cell lines (MCF-7, HCC1937) and three prostate factors that coordinate proliferation, differentiation, cancer cell lines. Compared to normal breast cells, we maturation and apoptosis of mammary epithelial cells. observe a high level constitutive expression of SOCS2, Exquisite control of the initiation, strength and duration SOCS3, SOCS5, SOCS6, SOCS7, CIS and/or SOCS1 of signals from the diverse array of cytokines and genes in the human cancer cells. In MCF-7 and HCC1937 growth factors in mammalian breast is essential to the breast-cancer cells, transcription of SOCS1 is dramati- timely initiation of the menstrual cycle, lactation or cally up-regulated by IFNc and/or ionizing-radiation breast lobule involution (Medina, 2005). Germ-line while SOCS3 is transiently down-regulated by IFNc and mutations or epigenetic mechanisms that silence pro- IGF-1, suggesting that SOCS genes are not silenced teins that regulate cytokine activities underlie breast in these cells by the epigenetic mechanism of DNA- tumorigenesis. This has led to interest in cytokine- hypermethylation. We further showthat the kinetics of signaling mechanisms and how they can be exploited to SOCS1-mediated feedback inhibition of IFNc signaling pharmacologically inhibit aberrantly activated human is comparable to normal breast cells, indicating that cancer cells. the SOCS1 protein in breast-cancer cells is functional. Most growth factors/cytokines implicated in patho- We provide direct evidence that STAT3 pathways are genesis of breast cancer share the common feature of constitutively activated in MCF-7 and HCC1937 cells and activating STAT pathways (Darnell, 1997; Clevenger, may drive the aberrant persistent activation of SOCS 2004). The 6-member STAT family of transcription genes in breast-cancer cells. Our data therefore suggest factors links cytokine signals to transcriptional events that elevated expression of SOCS genes is a specific that regulate cell-cycle progression and apoptosis lesion of breast-cancer cells that may confer resistance to (Bowman et al., 2000; Darnell, 2005). The strength proinflammatory cytokines and trophic factors, by and duration of STAT signals are regulated by suppres- shutting down STAT1/STAT5 signaling that mediate sor of cytokine-signaling (SOCS) proteins, an 8-member essential functions in the mammary gland. family of cytokine-inducible proteins that attenuate or Oncogene (2007) 26, 1941–1948. doi:10.1038/sj.onc.1209993; terminate cytokine/growth factor signals (Hilton, 1999). published online 25 September 2006 If not properly regulated, constitutive activation of STAT pathways can induce oncogenic transformation, tumor cell invasion and metastasis (Darnell, 2005; Haura et al., 2005). In fact, defects in negative-feedback regulation of STAT pathways have been identified in Correspondence: Dr MK Evans, Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes diverse tumors (Sutherland et al., 2004; Campbell, 2005; of Health, Baltimore, Maryland 21224, USA. Haura et al., 2005; Sultan et al., 2005). Recently, E-mail: [email protected] or hypermethylation of the SOCS1 or SOCS3 gene has Dr CE Egwuagu, Laboratory of Immunology, National Eye Institute, been reported in lung cancer (He et al., 2003), breast and National Institutes of Health, Bethesda, Maryland 20892, USA. E-mail: [email protected] ovarian cancer (Sutherland et al., 2004), squamous cell Received 29 April 2006; revised 9 August 2006; accepted 11 August 2006; carcinoma of the head and neck (Weber et al., 2005) and published online 25 September 2006 hepatocellular carcinoma (Niwa et al., 2005). This has SOCS genes are not silenced in breast-cancer cells MK Evans et al 1942 led to the speculation that SOCS genes are transcrip- tionally silenced during oncogenic transformation of epithelial carcinoma cells and that defective expression of SOCS proteins, with subsequent loss of feedback- regulation, may contribute to tumor progression and metastasis (Rottapel et al., 2002; He et al., 2003). In this study, we have utilized a panel of tumor cell lines to investigate whether: (i) SOCS genes are tran- scriptionally silent in breast and prostate cancer cells; (ii) whether negative-feedback responses mediated by SOCS proteins are normal or defective in breast-cancer cells. We show that SOCS genes are constitutively expressed at relatively high levels in human breast-cancer cells, indicating that SOCS promoters are not transcrip- tionally silent. Our data further indicates that elevated SOCS expression in breast-cancer cells derives from persistent activation of SOCS genes in response to constitutive activation of STAT3 pathways in these cells. Results SOCS genes are transcriptionally active and constitutively Figure 1 SOCS genes are transcriptionally active and constitu- tively expressed in breast and prostate cancer cells. (a) Ribonu- expressed in breast-cancer cells clease protection assay (RPA). (b) Real-time RT–PCR analysis of We utilized two breast-cancer cell lines (MCF-7 and normal human prostate cells (RWPE-1) or malignant prostate HCC1937) and a normal mammary epithelial cell line cancer cell lines (LNCaP, PC-3, DU-145). (AG11134) to examine whether transcriptional silencing of SOCS genes occurs frequently in human breast carcinoma cells. As a positive control, we also analysed a B-lymphoblastoid cell line (HCC1937BL) that consti- SOCS genes are constitutionally expressed, but also that tutively expresses high levels of most SOCS family genes the cancer cells are capable of inducing transcription of (unpublished data). The RPA data presented in Figure 1a SOCS genes in context of classical feedback response to reveals that most SOCS genes are constitutively expressed growth-factor/cytokine signaling. To this end, MCF-7, at high levels in the breast-cancer cells relative to the HCC1937 and AG11134 cells were starved for 12 h, normal breast cells. Although SOCS1, SOCS2 and stimulated with IFNg and then analyzed for induction SOCS3 genes are known to be hypermethylated in of SOCS expression. We show that IFNg activates MCF-7 cells (He et al., 2003; Sutherland et al., 2004), transcription of SOCS1 and CIS in these cells. On the this result clearly reveals that these genes are not other hand, SOCS3 expression is induced in AG11134 transcriptionally silent in MCF-7 cells. In addition, but downregulated in the two cancer cell lines at the SOCS2, SOCS3, SOCS5, SOCS6 and SOCS7 genes 120-min time point (Figure 2). However, moderate induc- are expressed in HCC1937 cells at levels comparable to tion of SOCS3 is also observed in HCC1937 at 30-min. MCF-7 (Figure 1a). We also analysed SOCS expression The complex pattern of SOCS5 or SOCS6 expression in a normal prostate cell line (RWPE-1) and three observed is consistent with the fact that these SOCS prostate cancer cell lines (LNCaP, PC-3 and DU-145) members are not classic feedback regulators of cytokine- and as shown in Figure 1b, SOCS1, SOCS3, SOCS5 and signaling and the mechanism of transcriptional regula- CIS genes are transcriptionally active in these cell lines, tion of both genes is poorly understood. These results albeit to varying extent. Both the PC-3 and DU-145 clearly suggest that SOCS promoters of the breast- express levels of SOCS1, SOCS3, SOCS5, CIS genes that cancer cells are responsive to cytokine-induced tran- are significantly lower than the normal RWPE prostate scriptional regulation as indicated by upregulation of cells. On the other hand, LNCaP cells express SOCS1, SOCS1 and CIS genes and downregulation of SOCS3 SOCS3, SOCS5 and CIS at levels comparable to RWPE, gene. underscoring the fact that this carcinoma cell line exhibits anormalpatternofSOCS genes expression. These results Duration of STAT signals is inversely correlated with SOCS indicate that genes are not silenced in all breast or SOCS levels in breast cells prostate cancer cells. To investigate whether SOCS proteins in breast-cancer cells are capable of mediating feedback-inhibition of Interferon-g activates transcription of SOCS genes in cytokine-signaling, we stimulated MCF-7, HCC1937, MCF-7 or HCC1937 cells HCC1937BL and AG11134 cells with IFNg for varying To demonstrate that SOCS genes are not silenced in amounts of time and determined the kinetics of STAT1 breast-cancer
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