title: EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses' Health Studies.
abstract: 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. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort.
  
  
  
  We 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.
  
  
  
  Women 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).
  
  
  
  These 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.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, 02215, MA, USA. fbeca@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, 02215, MA, USA. fbeca@bidmc.harvard.edu.|Harvard Medical School, Boston, 02215, MA, USA. fbeca@bidmc.harvard.edu.
authors.forename: Francisco
authors.identifier: 0000-0002-4409-012X
authors.initials: F
authors.lastname: Beca
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kensler
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, 02215, MA, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, 02215, MA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glass
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, 02215, MA, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, 02215, MA, USA.|Harvard Medical School, Boston, 02215, MA, USA.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, 02215, MA, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, 02215, MA, USA.|Harvard Medical School, Boston, 02215, MA, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D001706:Biopsy; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000209:etiology*; D016022:Case-Control Studies; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D009726:Nurses; D016017:Odds Ratio; D011159:Population Surveillance; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012306:Risk
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: Benign breast disease; Breast Cancer; EZH2; Nurses’ Health Studies; Risk