Background Mesothelin previously shown to be expressed in triple negative breast cancer (TNBC) is a potential therapeutic target and prognostic marker in breast cancer. hazard (Cox-PH) model to adjust for the two independent predictors of survival namely (+) axilla lymph nodes and tumor size and we found a significant association between mesothelin expression and overall and disease-specific survival in the discovery cohort (HR = 3.06 95 CI 1.40-6.68). Using the TCGA dataset we confirmed that over a median follow-up of 16.0 months patients with mesothelin-expressing tumors had poorer overall survival (HR=1.46; 95% CI 1.05-2.03). On Cox-PH multivariate analysis mesothelin-positivity was an independent predictor of worse survival after adjusting for (+) axillary lymph nodes and tumor size (HR = 1.69; 95%CI 1.17-2.42). Conclusions Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in TNBC tumors especially in African American women. As there is no existing targeted therapy for TNBC mesothelin may be a promising drug target for TNBC. Future work is needed to evaluate the efficacy of mesothelin directed targeted therapy in the treatment of breast cancer. gene which was first identified as a cell surface antigen recognized by the mouse K1 monoclonal antibody [1]. Mesothelin was subsequently cloned by Chang and Pastan who were the first to show its expression on the surface of human ovarian carcinoma cells [2]. Mesothelin is initially synthesized as a 69kDa precursor protein which is subsequently cleaved post-translationally into a 40 kDa membrane-bound C-terminal fragment mesothelin and a 31 kDa N-terminal soluble secreted protein fragment megakaryocyte potentiating factor (hMPF) CEP-18770 [3]. Mesothelin is expressed in the lining of the peritoneum pleura and pericardium [1]. The biological function of mesothelin is unknown but mice with homozygous null Cd24a mutation showed no detectable anatomic developmental or reproductive defects indicating that mesothelin is not likely to be an essential protein in mice [4]. Mesothelin appears to be involved in cell adhesion via its interaction with CA125 and has been proposed to play a role in cancer progression [5]. Only recently has mesothelin been identified as a tumor antigen in breast cancer [6-8] in part because tumors of the most common breast cancer subtype CEP-18770 i.e. luminal A rarely express mesothelin. In contrast mesothelin is expressed in nearly half of all tumors belonging to the less common breast cancer subtype basal or triple negative breast cancer (TNBC) [8]. This skewed expression pattern of mesothelin suggests that mesothelin may be a unique therapeutic target in TNBC. As numerous targeted therapeutic strategies directed against mesothelin have been developed for the treatment of malignancies such as mesothelioma ovarian and some biliary CEP-18770 and pancreatic carcinoma (summarized in a recent review [9]) these strategies which include mesothelin-specific immune toxins monoclonal CEP-18770 antibodies antibody-drug conjugates tumor vaccines and cell-based immunotherapies may be adopted as novel treatment strategies for TNBC. However prior to adopting these mesothelin directed targeted therapy for clinical use the mechanistic role of mesothelin in breast cancer pathogenesis has to be better understood. The association between mesothelin expression in tumor cells and unfavorable clinical outcome has been reported in several gastrointestinal malignancy including biliary adenocarcinoma [10] and gastric carcinoma [11]. However there has also been conflicting results that demonstrated that mesothelin expression was associated with prolonged survival in patients with advanced stage in epithelial ovarian carcinomas [12]. As for breast cancer efforts to elucidate its prognostic significance have likely been dampened due to conflicting results from two studies aimed at evaluating the association between mesothelin expression and clinical outcomes in breast cancer [13 14 We therefore performed this study using data from two breast cancer patient cohorts comprising of patients treated at a single institution (n=141 discovery cohort) and patients from a multi-center cohort (n=844 validation cohort) obtained from The Cancer Genome Atlas (TCGA) to further clarify the equivocal status of mesothelin as a prognostic tumor marker in breast cancer. Our results demonstrate that mesothelin is indeed a prognostic tumor marker in breast cancer. Our findings support the need for further research to elucidate the mechanistic role of mesothelin in breast cancer progression and to.