Abstract 4895: Component of the gene silencing machinery: SMCX/JARID1C a new prognostic marker for breast cancer

Abstract

Abstract Background: Histone demethylase enzymes contribute to cancer cell lines proliferation. These enzymes have the capacity to regulate not only the modification itself but also function indirectly to antagonize binding of effectors proteins to modified chromatin. JARID1C, a demethylase enzyme encoded by X-chromosome and belonging to the poorly described JARID1 family protein, was specific to the methylation of Lys4 of histone H3 (H3K4). Few is known about the molecular function of JARID1C with the exception that it escapes X inactivation and is mutated in X-linked mental retardation. In this study, we evaluated the incidence of JARID1C during the progression of breast cancer (BC) disease, and investigated its potential prognostic value. Methods: Gene expression was evaluated by qRT-PCR in paraffin-embedded samples: 11 normal breast samples, 66 ductal carcinoma in situ (DCIS), 212 primary BC and 11 metastatic lesions from primary BC. H3K4me3 status was assessed by immunohistochemistry. Results: JARID1C mRNA level was statistically higher in BC disease compared to normal breast tissue (p<0.002) but no differences were observed between DCIS, invasive and metastatic lesions. In invasive BC, mRNA levels of JARID1C were lower in the basal subgroup (ER-/HER2-) as compared to the other subgroups (luminal-A p=0.139, luminal-B p=0.018, HER2 p=0.008). High mRNA levels of JARID1C (continuous variable) were statistically associated with a higher risk of distant metastasis (HR=1.3, 95%CI:[1.05-1.6], p=0.013). In multivariate analysis, JARID1C (HR=1.84, 95%CI:[1.23-2.76], p=0.003) and nodal status (HR=3.89, 95%CI:[1.349-11.238], p=0.012) were the only covariates with a significant prognostic value. Similar results were observed when JARID1C was considered as a dichotomous variable (quartiles) in all patients (HR= 2.569, 95%CI:[1.377-4.792], p=0.003) as well as in the ER+ (HR= 3.008, 95%CI:[1.414-6.44], p=0.005) and the node+ subgroups (HR=3.622, 95%CI:[1.671-7.851], p=0.001). JARID1C remained significant in the multivariate analysis (HR=3.337, 95%CI:[1.635-6.811], p=0.001) together with nodal status (HR=3.877, 95%CI:[1.865-8.058], p=0.0003). The global demethylase expression (median expression of other H3K4 demethylases i.e. LSD1, JARID1A and JARID1B) was statistically decreased by 84% (p<10-6) in the patients of good prognosis (JARID1C low expression). These results are in agreement with the fact that H3K4me3 methylation was higher in the patients with low JARID1C expression, although non significant. Discussion. Alteration of JARID1C expression levels is observed already at the DCIS stage highlighting the important role of epigenetic machinery during breast tumorigenesis. Of interest, JARID1C over expression is associated with poor clinical outcome and adds independent prognostic information to the current prognostic biomarkers in BC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4895.