title: Clinical and biological relevance of enhancer of zeste homolog 2 in triple-negative breast cancer.
abstract: The polycomb group protein, enhancer of zeste homolog 2, is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of enhancer of zeste homolog 2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with the enhancer of zeste homolog 2, cytokeratin 5/6, epidermal growth factor receptor 1, and p53. The expression of these markers was correlated with clinicopathologic variables and patients' outcome. Furthermore, in vivo enhancer of zeste homolog 2 gene silencing was achieved using small interfering RNA incorporated into chitosan nanoparticles. Of 261 cases of invasive breast cancer, high expression of the enhancer of zeste homolog 2 was detected in 87 (33%) cases, and it was strongly associated with a triple-negative breast cancer phenotype (P < .001) compared with all other non-triple-negative breast cancers. Furthermore, high enhancer of zeste homolog 2 was significantly associated with high histologic grade (P = .01), estrogen receptor negativity (P < .001), progesterone receptor negativity (P < .001), epidermal growth factor receptor positivity (P = .04), and high p53 expression (P < .001). Survival analysis demonstrated that patients with high enhancer of zeste homolog 2 had a poorer overall survival compared with those with low enhancer of zeste homolog 2 (P = .03), and it retained its significance as an independent prognostic factor (P = .02). In addition, enhancer of zeste homolog 2 gene silencing resulted in a significant reduction in tumor growth (P < .01) in the orthotopic MB-231 mouse model of breast carcinoma. Our results show that high enhancer of zeste homolog 2 expression is significantly associated with triple-negative breast cancer and decreased survival. Enhancer of zeste homolog 2 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation.
authors.affiliation: Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yaser R
authors.initials: YR
authors.lastname: Hussein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Bassam
authors.initials: B
authors.lastname: Albashiti
authors.forename: Assaad
authors.initials: A
authors.lastname: Semaan
authors.forename: Zeina
authors.initials: Z
authors.lastname: Nahleh
authors.forename: Juwon
authors.initials: J
authors.lastname: Roh
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C498409:EZH2 protein, human; C508053:ERBB2 protein, human