title: Aberrant expression of enhancer of zeste homologue 2, correlated with HIF-1α, refines relapse risk and predicts poor outcome for breast cancer.
abstract: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior in a variety of cancers. In vitro, hypoxia-inducible factor 1α (HIF-1α) transcriptionally activates EZH2 and promotes the progression of breast tumor initiating cells. Here, we characterized the clinicopathological effect of EZH2 and HIF-1α in 410 breast cancer patients. We examined EZH2 and HIF-1α expression using immunohistochemistry and western blotting. We found that EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with lymphatic invasion (P=0.025), HER2 expression (P=0.005) and hypoxia (P<0.001). Overexpression of EZH2 predicted a poor 5-year overall survival (OS, 74.8 vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2 vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7 vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4 vs. 90.5%, P=0.039). Multivariate analysis confirmed that EZH2 is an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was identified between EZH2 and HIF-1α (r=0.299, P<0.001). Importantly, tumors coexpressing HIF-1α and EZH2 had a poorer OS (P=0.007). In conclusion, our study demonstrated that EZH2 is an independent negative prognostic biomarker for breast cancer. Tumors overexpressing HIF-1α and EZH2 are more prone to disease progression.
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Pathology, Gastrointestinal Institute, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China.
authors.forename: Xin-Juan
authors.initials: XJ
authors.lastname: Fan
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Zhan-Hong
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Jing-Yun
authors.initials: JY
authors.lastname: Wen
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Ma
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Dan-Yun
authors.initials: DY
authors.lastname: Ruan
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Ze-Xiao
authors.initials: ZX
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510065, P.R. China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Xiang-Yuan
authors.initials: XY
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P.R. China.
authors.forename: Xiang-Bo
authors.initials: XB
authors.lastname: Wan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D017254:Leukemic Infiltration / Q000378:metabolism / Q000473:pathology*; D061986:MCF-7 Cells; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2