Abstract\nBackground: Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell\nrenewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and\nhas been suggested to identify normal breast epithelium at increased risk of breast cancer development. However,\nthe association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been\nevaluated in a large prospective cohort.\nMethods: We examined the association between EZH2 protein expression and subsequent breast cancer risk using\nlogistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the\nNursesââ?¬â?¢ Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was\nevaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting\nfor matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index.\nResults: Women with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a\nsignificantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11ââ?¬â??7.84)\ncompared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased\nfor each 5% increase in EZH2 [removed]OR 1.22, 95% CI 1.02ââ?¬â??1.46, p value 0.026). Additionally, women with high\nEZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to\nwomen with low EZH2 and low ER [removed]OR 4.02, 95% CI 1.29ââ?¬â??12.59).\nConclusions: These results provide further evidence that EZH2 expression in the normal breast epithelium is\nindependently associated with breast cancer risk and might be used to assist in risk stratification for women with\nbenign breast biopsies.
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