EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development

Abstract

It is well established that benign proliferative lesions and atypical hyperplasia increase the risk of breast cancer, which can develop in either breast. At present, there is no radiological, pathological, or molecular marker capable of distinguishing which proliferative or atypical lesions will progress to carcinoma. EZH2, a protein involved in stem cell renewal and carcinogenesis is upregulated in the morphologically normal breast epithelium from BRCA1 mutation carriers. Here, we tested the hypothesis that EZH2 expression alone or in combination with the breast stem cell marker aldehyde dehydrogenase-1 (ALDH-1) may identify benign breast biopsies that progress to breast cancer in the future. Benign breast biopsy samples obtained from 59 women who subsequently developed (study group, n ¼ 29) or who did not develop (control group, n ¼ 30) breast cancer in the same time period were subjected to immunohistochemical analyses of EZH2 and ALDH-1 proteins. When present, EZH2 was expressed in the nuclei of benign epithelial cells, whereas ALDH-1 was expressed in the cytoplasm of epithelial cells and/or in the stroma. EZH2, epithelial ALDH-1, and expanded stromal ALDH-1-positive cells were present in 95, 43, and 69%, respectively, of study group biopsies, compared with 16, 13, and 37%, respectively, of control biopsies (P o0.05 for all). The mean percentage of EZH2-positive cells was higher in the study group than in the control group (34 and 6%, respectively). EZH2 expression was associated with breast cancer development (P ¼ 8.2 Â 10 À6 ) and with younger age at cancer diagnosis (P ¼ 0.0086). Both stromal and epithelial ALDH-1 were associated with development of breast cancer (P ¼ 0.001 and P ¼ 0.049, respectively). Our study provides first evidence that EZH2 and epithelial and stromal ALDH-1 detection in benign breast biopsies may predict increased risk for breast cancer, with implications for breast cancer prevention.

The histone methyltransferase EZH2 promotes mammary stem and luminal progenitor cell expansion, metastasis and inhibits estrogen receptor-positive cellular differentiation in a model of basal breast cancer

“…EZH2 is associated with younger age at breast cancer diagnosis (29), increased tumor size, high histopathologic grade, negative hormone receptor status, epidermal growth factor receptor and Her2 overexpression, p53 mutations, lymphatic invasion, poor survival and metastasis (30)(31)(32). Our results demonstrated that EZH2 activity was associated with lung metastasis in a model of basal breast cancer.…”

Expression and clinical implications of enhancer of Zeste homolog 2 and p53 protein in squamous cell carcinoma and precancerous lesions in the cervix

“…This implies that EZH2 expression is related to tumor invasion and metastasis (Visser et al, 2001;Hoffmann et al, 2007;Kunju et al, 2011). Bachmann et al (2006) and Zhang et al (2006) also demonstrated that EZH2 promoted the occurrence, development, and invasion of endometrial carcinoma.…”

High Expression of Stem Cell Marker ALDH1 is Associated with Reduced BRCA1 in Invasive Breast Carcinomas

“…Moreover, Kunju et al (2011) in very recent study presented primary evidence that epithelial and stromal ALDH1 detection in benign breast biopsies may predict increased risk for breast cancer, which may have implications for breast cancer prevention.…”