SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL

✍ Scribed by Johanna L. Barclay; Stephen T. Anderson; Michael J. Waters; Jon D. Curlewis

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: French
• Weight: 589 KB
• Volume: 124
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.24172

✦ Synopsis

Abstract

Suppressor of cytokine signaling 3 (SOCS3), as a key regulator of cytokine signaling, has the potential to modulate numerous cellular processes. Its involvement in inflammatory disease is well established, and there is increasing evidence for a role in breast cancer as a regulator of signal transducers and activators of transcription (STATs). Here we show that over‐expression of SOCS3 markedly supresses STAT3 expression, and abrogates STAT5 phosphorylation, resulting in decreased cell proliferation in T47D breast cancer cells, and decreased proliferation and anchorage‐independent growth in MCF7 cells. Using T47D cells, we elucidated the signaling pathways and transcription factors involved in SOCS3 expression in response to prolactin, a key mammotropic hormone. Quantitative real time PCR was used to examine SOCS3 mRNA expression, IP/WB was used to examine STAT phosphorylation, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and gel shift assays allowed evaluation of cis‐elements and trans‐factors regulating SOCS3 expression. We demonstrate that prolactin‐induced SOCS3 expression is STAT‐dependant, predominantly involving STAT5, although STAT1 is also associated with the promoter. In addition, prolactin‐induced SOCS3 promoter activation requires PKA‐stimulated Sp1 binding to the GC‐rich region of the promoter. Finally, we show that PRL‐induced SOCS3 expression can be potentiated by co‐treatment with PGE~2~. This study demonstrates that SOCS3 acts as an anti‐proliferative agent in breast cancer cells, and highlights the complexity of SOCS3 regulation and crosstalk. © 2008 Wiley‐Liss, Inc.