Abstract
BackgroundEnhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort.MethodsWe examined the association between EZH2 protein expression and subsequent breast cancer risk using logistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses’ Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was evaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting for matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index.ResultsWomen with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a significantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11–7.84) compared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased for each 5% increase in EZH2 expression (OR 1.22, 95% CI 1.02–1.46, p value 0.026). Additionally, women with high EZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to women with low EZH2 and low ER expression (OR 4.02, 95% CI 1.29–12.59).ConclusionsThese results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies.
Highlights
Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis
The intraclass correlation coefficient (ICC) across cores was 0.69 in the epithelium and 0.64 in stroma, suggesting moderately low heterogeneity in EZH2 expression across the cores
Stromal and epithelial expression of EZH2 in normal breast tissue were moderately correlated (Spearman r = 0.79, p < 0.001) and the distribution of the EZH2 expression in both the normal epithelium and stroma was similar across participants independent of the concomitant benign breast disease (BBD) diagnosis category (Additional file 1: Figure S4)
Summary
Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. Due to its role in regulating fundamental cellular processes, such as cell cycle regulation, senescence and differentiation, EZH2 has been thought to contribute to malignant transformation. This view has been challenged and it has been suggested that high EZH2 is a consequence rather than a cause of cancer [9]
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