Prognostic influence of cyclooxygenase-2 protein and mRNA expression in node-negative breast cancer patients

Abstract

BackgroundCyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression. The aim of this study was to analyze the prognostic impact of COX-2 expression in a cohort of lymph node-negative breast cancer patients not treated in the adjuvant setting.MethodsCOX-2 expression was determined by immunohistochemistry (IHC) in tumor tissue of 193 node-negative breast cancer patients. Additionally, mRNA expression was determined in corresponding tumor samples using microarray based gene-expression data. Univariate and multivariate Cox regression analyses adjusted for age at diagnosis, tumor size, histological grade, human epithelial growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) were performed to evaluate the association of both COX-2 protein and mRNA expression with survival. Survival rates were determined by the Kaplan-Meier method. Correlations between COX-2 expression and established prognostic factors were analyzed using the Chi-square test. A potential correlation between COX-2 protein expression and COX-2 mRNA expression was assessed utilizing the Kruscal-Wallis-H-test.ResultsCOX-2 protein expression was positive in 24.9% of the breast cancer samples. Univariate analysis showed that COX-2 protein expression was associated with shorter disease-free survival (DFS) (P = 0.0001), metastasis-free survival (MFS) (P = 0.002) as well as breast cancer specific overall survival (OS) (P = 0.043). In multivariate analysis COX-2 expression retained its significance independent of established prognostic factors for shorter DFS (P < 0.001, HR = 2.767, 95% CI = 1.563-4.901) and for inferior MFS (P = 0.002, HR = 2.7, 95% CI = 1.469-5.263) but not for OS (P = 0.096, HR = 1.929, 95% CI = 0.889-4.187). In contrast, COX-2 mRNA expression was not related to survival and failed to show a correlation with protein expression (P = 0.410).ConclusionsThe present findings support the hypothesis that COX-2 protein but not mRNA expression is associated with an unfavorable outcome in node-negative breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-952) contains supplementary material, which is available to authorized users.

The prognostic impact of COX‐2 expression in breast cancer depends on oral contraceptive history, preoperative NSAID use, and tumor size

“…The association between COX‐2 expression and prognosis remained significant after multivariable adjustments only in two smaller studies with around 200 patients, but not in the two largest studies with 1,576 and 2,001 patients, respectively . In other studies, COX‐2 was only independently associated with worse prognosis in subgroups of patients who were either node‐negative, had high Ki67, ER‐negative, or ER‐positive tumors . There are many possible explanations for the diverse results between previous studies including study populations with different body constitutions, reproductive patterns, lifestyle factors, medication use, ethnic backgrounds, and study end‐points.…”

“…Tumor COX‐2 expression has previously been associated with a shorter disease‐free survival in many but not all studies. However, most of the previous studies had 200 patients or less . Further, multivariable analyses to elucidate the independent prognostic value of COX‐2 expression, were only performed in a subset of these studies .…”

“…However, most of the previous studies had 200 patients or less . Further, multivariable analyses to elucidate the independent prognostic value of COX‐2 expression, were only performed in a subset of these studies . The association between COX‐2 expression and prognosis remained significant after multivariable adjustments only in two smaller studies with around 200 patients, but not in the two largest studies with 1,576 and 2,001 patients, respectively .…”

“…COX‐2 expression in predominantly ER‐negative tumors was shown to lead to Akt‐pathway activation . Regarding prognosis, most, but not all, studies have found an association between high COX‐2 expression and worse prognosis. Whether COX‐2 expression was associated with prognosis in the different studies also depended on tumor characteristics, type of breast cancer treatment, body constitution, and concomitant medications .…”

Cyclooxygenase‐2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy

“…One key inflammatory mediator deregulated in many cancers is cyclooxygenase-2 (COX-2). Elevated COX-2 expression, and that of its principle metabolic product prostaglandin E2 (PGE 2 ), has been shown to be inversely associated with patient survival [25–27]. Epidemiological, clinical, and preclinical studies have shown that the inhibition of PGE 2 synthesis through the use of either nonsteroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors has the potential to reduce the risk of developing certain cancers, including breast, head and neck squamous cell carcinoma, osteosarcoma, pancreas, and prostate cancers, and to reduce the mortality caused by these cancers [28–35].…”