Aberrant inducible nitric oxide synthase expression predicts poor survival in estrogen receptor negative breast cancer, and is associated with a gene expression signature similar to that of basal-like breast cancer.

Abstract

Abstract Abstract #5067 Background: Inducible nitric oxide synthase (iNOS) is a key enzyme in the inflammatory process, that catalyses the production nitric oxide (NO). NO is a free radical that affects the redox state of tumor cells and thus cell signaling. We hypothesized that iNOS expression is associated with markers of outcome and influences breast cancer survival by estrogen receptor (ER) α-independent mechanisms.
 Method: 248 cases of incident breast cancer were examined by IHC for iNOS expression. Univariate and multivariate analyses were performed to assess correlations between iNOS expression and clinico-pathological features of breast cancer, and patient survival. In addition, 35 tumors were laser capture microdissected and the effect of iNOS on gene expression profiles analyzed by Affymetrix gene expression arrays.
 Results: iNOS was moderately to strongly expressed in the majority of breast tumors (70%). iNOS was significantly associated markers of poor prognosis including p53 mutation accumulation, increased microvessel density, and high tumor grade. iNOS was not associated with race/ethnicity (143 African American, 105 Caucasian). In Cox regression analysis, high levels of iNOS expression was a predictor of both 5-year (Hazard Ratio - 5.41; 95% C.I. 1.25 to 23.48) and 10-year (H.R. 4.63; 95% C.I. 1.36 to 15.73) breast cancer-specific survival in women with ER-negative tumors. iNOS was not a predictor of ER positive breast cancer survival. Neither tumor p53 status nor chemotherapy modified these associations. Gene expression analysis identified changes in significant changes in gene expression with high levels of iNOS expression in ER negative breast cancer. This observation was not seen in ER positive breast cancer.
 44% of the iNOS associated genes had previously been found to be associated with the ER negative breast cancer subtype, basal-like breast cancer phenotype.
 Discussion: These results suggest that iNOS contributes to the pathogenicity of ER-negative breast cancers and is a predictor of patient survival. The similarity of the iNOS induced gene signature to that of basal-like breast cancer, suggests that iNOS may play a role in the aggressive nature of basal-like breast cancer and may be a potential therapeutic target for the treatment of ER negative and basal-like breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5067.