Abstract A15: High miRNA-26a and low EZH2 expression levels are associated with favorable outcome to tamoxifen in advanced breast cancer

Abstract

Abstract Background: In breast cancer we have recently discovered that decreased EZH2 expression levels are associated with a favorable outcome to tamoxifen in advanced disease. Furthermore, EZH2 knockdown in the breast cancer cell line MCF7 resulted in estrogen receptor (ER) upregulation and increased sensitivity to anti-estrogens. Interestingly, EZH2 has been identified as target of miRNA-26a and miRNA-101. Objective: The main objective of this study is to investigate miRNA-26a and miRNA-101 for: A) their association with EZH2 and B) their predictive value in breast cancer patients treated with first-line tamoxifen monotherapy. Materials & Methods: Expression levels of miRNA-26a, miRNA-101, EZH2 and references were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in 235 ER-positive primary breast cancer specimens from patients with advanced disease. The levels of expression were related to clinicopathologic factors and disease outcome. Computations were performed with STATA and P-values <0.05 were considered statistically significant. Results: Expression levels of miRNA-26a and miRNA-101 were not correlated with age, tumor grade, tumor size, and nodal status. The miRNA-26a levels were significantly associated with progesterone (PgR) levels, HER2-status and EGFR levels, whereas miRNA-101 levels showed significant relations with PgR expression and menopausal status. The miRNA-26a and miRNA-101 levels showed an inverse relation with EZH2 mRNA levels (Spearman Rank Correlation of −0.21 and −0.15, respectively, P<0.05). As continuous variable in univariate analysis, miRNA-26a (Hazard Ratio (HR)=0.13, 95% CI: 0.06-0.28) correlated with Time To Progression (TTP), whereas miRNA-101 did not (HR=0.87, 95% CI: 0.70-1.07). In multivariate analysis including traditional predictive factors, the tertile with highest miRNA-26a levels (HR=0.51, 95% CI: 0.35-0.75) alone, and combined with the tertile with lowest EZH2 levels (HR=0.59, 95% CI: 0.41-0.85) were associated with a favorable TTP independently of traditional factors. Conclusion & Discussion: The miRNA-26a and miRNA-101 levels have an inverse relation with EZH2, but only miRNA-26a has predictive value in advanced breast cancer. High levels of miRNA-26a and low EZH2 levels are associated with a favorable outcome to tamoxifen therapy. Interestingly, estrogens repress miRNA-26a expression suggesting that ER-positive tumors have less miRNA-26a than ER-negative tumors. This contradicts, however, with the lower EZH2 levels observed in ER-positive compared to ER-negative breast cancers. To clarify this paradox, future (functional) studies will focus on miRNA-26a and EZH2 in different breast cancer subtypes and determine their activated pathways in relation with response to anti-estrogens. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A15