1. ¹Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
2. ²Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr MK Evans or Dr CE Egwuagu, Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. E-mail: evansmi@grc.nia.nih.gov or Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. E-mail: egwuaguc@nei.nih.gov

Received 29 April 2006; Revised 9 August 2006; Accepted 11 August 2006; Published online 25 September 2006.

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 IFN, 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 IFN and/or ionizing-radiation while SOCS3 is transiently down-regulated by IFN 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 IFN 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.