%0 Journal Article
%T Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer
%A Christopher H Switzer
%A Robert Y-S Cheng
%A Lisa A Ridnour
%A Sharon A Glynn
%A Stefan Ambs
%A David A Wink
%J Breast Cancer Research
%D 2012
%I BioMed Central
%R 10.1186/bcr3319
%X Promoter region analyses were performed on genes upregulated in inducible nitric oxide synthase (NOS2) high expressing tumors for Ets-binding sites. In vitro mechanisms were examined in human basal-like breast cancer cells lines. NO signaling effects were studied using either forced NOS2 expression or the use of a chemical NO-donor, diethlylenetriamine NONOate (DETANO).Promoter region analysis of genes that are up-regulated in human ER-negative breast tumors with high NOS2 expression revealed that the Ets-binding sequence is the only common promoter element present in all of these genes, indicating that Ets-1 is the key transcriptional factor down-stream of oncogenic NOS2-signaling. Accordingly, both forced NOS2 over-expression and exposure to NO-donors resulted in significant Ets-1 transcriptional activation in ER- breast cancer cells. Functional studies showed that NO activated Ets-1 transcriptional activity via a Ras/MEK/ERK signaling pathway by a mechanism that involved Ras S-nitrosylation. RNA knock-down of Ets-1 suppressed NO-induced expression of selected basal-like breast cancer markers such as P-cadherin, S100A8, IL-8 and ¦Á¦Â-crystallin. Additionally, Ets-1 knock-down reduced NO-mediated cellular proliferation, matrix metalloproteinase and cathepsin B activities, as well as matrigel invasion.These data show that Ets-1 is a key transcriptional mediator of oncogenic NO signaling that promotes the development of an aggressive disease phenotype in ER- breast cancer in an Ets-1 and Ras-dependent manner, providing novel clues of how NOS2 expression in human breast tumors is functionally linked to poor patient survival.Inducible nitric oxide synthase (NOS2) is a pro-inflammatory enzyme generally with a key function in the innate immune response [1]. However, NOS2 expression is up-regulated and associated with poor outcome in many human cancers, such as melanoma, glioma and colon cancer [2-4]. Recently, we reported that high NOS2 expression is a predictor of poor pa
%U http://breast-cancer-research.com/content/14/5/R125