Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer

Breast cancer research: BCR (Impact Factor: 5.49). 09/2012; 14(5):R125. DOI: 10.1186/bcr3319
Source: PubMed


The Ets-1 transcription factor is a candidate breast cancer oncogene that regulates the expression of genes involved in tumor progression and metastasis. Ets-1 signaling has also been linked to the development of a basal-like breast cancer phenotype. We recently described a nitric oxide (NO)-induced gene signature that is associated with poor disease outcome in estrogen receptor-negative (ER-) breast cancer and contains both stem cell-like and basal-like components. Thus, we examined the role of Ets-1 in NO signaling and NO-induced phenotypes in ER- human breast cancer cells.

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 αβ-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.

Download full-text


Available from: Lisa A Ridnour
  • Source
    • "Nitrotyrosine, a biomarker of NO, was found to be correlated with VEGF-C expression and lymph node metastasis in breast cancer suggesting the role of NO in progression of breast carcinoma [33]. Switzer et al. showed that NOS2 expression in human breast tumors is functionally linked to poor patient survival [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO), is a ubiquitous, water soluble, free radical gas, which plays key role in various physiological as well as pathological processes. Over past decades, NO has emerged as a molecule of interest in carcinogenesis and tumor growth progression. However, there is considerable controversy and confusion in understanding its role in cancer biology. It is said to have bothtumoricidal as well as tumor promoting effects which depend on its timing, location, and concentration. NO has been suggested to modulate different cancer-related events including angiogenesis, apoptosis, cell cycle, invasion, and metastasis. On the other hand, it is also emerging as a potential anti-oncogenic agent. Strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain are being investigated. However, further validation and experimental/clinical trials are required for development of novel strategies based on NO for cancer treatment and prevention. This review discusses the range of actions of NO in cancer by performing an online MEDLINE search using relevant search terms and a review of the literature. Various mechanisms by which NO acts in different cancers such as breast, cervical, gastric,colorectal, and head and neck cancers are addressed. It also offers an insight into the dichotomous nature of NO and discusses its novel therapeutic applications for cancer prevention and treatment.
    Full-text · Article · May 2013 · World Journal of Surgical Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammation within the tumor microenvironment is a major driver of tumor progression and poor prognosis. Inducible nitric oxide synthase (NOS2) is present in numerous solid tumors. Estrogen receptor-negative (ER-) patients with high expression of tumor NOS2 have a poorer outcome than patients with low expression of NOS2. Furthermore, expression of NOS2 is associated with the basal-like breast cancer phenotype. Using an in vitro model, we have found that nitrosation of critical thiols and nitration of tyrosines lead to the activation of membrane receptors such as epithelial growth factor receptor, Src, Ras, and CD63. These nitric oxide-mediated events in itiate oncogenic signaling pathways such as PI3K/Akt, Ras/ERK, β-catenin, nuclear factor-κB, and AP-1. These data suggest that NOS2 can serve as a major "nonmutatational driver" of ER- breast cancer.
    Full-text · Article · Jan 2012 · Forum on immunopathological diseases and therapeutics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated expression of nitric oxide synthase 2 has been recently shown to correlate with poor survival in estrogen receptor-negative breast cancer. In an article in Breast Cancer Research, Switzer and colleagues identify the transcription factor Ets-1 as a critical mediator of nitric oxide-dependent oncogenic gene expression in basal-like breast cancer. This pathway is driven by S-nitrosylation of wild-type Ras, which leads to mitogen-activated protein kinase-dependent phosphorylation and activation of Ets-1. These results establish a new role for S-nitrosylation in mediating an aggressive breast cancer phenotype.
    Preview · Article · Nov 2012 · Breast cancer research: BCR
Show more