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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 volume 26, pages 1941–1948 (2007)Cite this article

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

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Acknowledgements

This research was funded by the Intramural Research Programs of the NIH, NIA and NEI. Authors thank Dr Simon Nyaga for technical assistance and critical reading of manuscript and Dr Patrice Morin for critical reading of the manuscript.

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Authors and Affiliations

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

    M K Evans, A Lohani & A R Trzeciak

  2. Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    C-R Yu, R M Mahdi, X Liu & C E Egwuagu

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  1. M K Evans
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  2. C-R Yu
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  3. A Lohani
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  4. R M Mahdi
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  7. C E Egwuagu
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Correspondence to M K Evans.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Evans, M., Yu, CR., Lohani, A. et al. Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals. Oncogene 26, 1941–1948 (2007). https://doi.org/10.1038/sj.onc.1209993

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