Expression of enhancer of zeste homologue 2, correlated with HIF-1α, to refine relapse risk and predict poor outcome for breast cancer.

Abstract

538 Background: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior for breast cancer. In vitro, hypoxia-inducible factor 1 alpha (HIF-1α) transcriptionally activates EZH2 and promotes breast tumor initiating cells progression. Here, we characterized the clinicopathological effect of HIF-1α and EZH2 in breast cancer patients. Methods: Tumor specimens from 410 luminal subtype breast cancer patients were used to construct tissue microarray. EZH2 and HIF-1α level were examined by immunohistochemistry staining and Western blot analysis. With the 5-year follow up, the prognostic effect of EZH2 was subjected to multivariate analysis. Results: EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with high histological grade (P=0.030), lymphatic invasion (P=0.025), HER2 overexpression (P=0.005) and hypoxic condition (P<0.001). Forced expression of EZH2 predicted a poor 5-year overall survival (OS, 74.8% vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2% vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7% vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4% vs. 90.5%, P=0.039). However, the prognostic effect of HIF-1α was not detected for breast cancer. Cox multivariate analysis confirmed that EZH2 was an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was detected between EZH2 and HIF-1α (r=0.299, P<0.001). Importantly, tumors with HIF-1α and EZH2 co-overexpression were correlated with a worsened OS (P=0.007). Conclusions: EZH2 was an independent negative prognostic biomarker for luminal subtype breast cancer. Targeting HIF-1α transcriptionally regulated EZH2 pathway might be of benefit in the treatment of luminal subtype of breast cancer.