title: High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer.
abstract: For patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their association with molecular pathways and with efficacy of tamoxifen as first-line monotherapy for metastatic breast cancer. Expression levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens of 235 estrogen receptor-α (ER)-positive patients. Pathway analysis was performed on microarray data available for 65 of these tumors. Logistic regression and Cox uni- and multivariate analysis were performed to relate expression levels with clinical benefit and time to progression (TTP). Increasing levels of miR-26a were significantly (P < 0.005) associated with both clinical benefit and prolonged TTP, whereas miR-101 was not. Cell cycle regulation and CCNE1 and CDC2 were the only significant overlapping pathway and genes differentially expressed between tumors with high and low levels of miR-26a and EZH2, respectively. In addition, increasing mRNA levels of CCNE1 (P < 0.05) and CDC2 (P < 0.001) were related to poor outcome. Multivariate analysis revealed miR-26a and CDC2 as an optimal set of markers associated with outcome on tamoxifen therapy, independently of traditional predictive factors. To summarize, only miR-26a levels are related with treatment outcome. Cell cycle regulation is the only overlapping pathway linked to miR-26a and EZH2 levels. Low mRNA levels of EZH2, CCNE1, and CDC2, and high levels of miR-26a are associated with favorable outcome on tamoxifen.
authors.affiliation: Department of Medical Oncology, Josephine Nefkens Institute and Cancer Genomics Center, Erasmus Medical Center Rotterdam, Room Be401, PO Box 2040, 3000 CA Rotterdam, The Netherlands. m.p.h.m.jansen@erasmusmc.nl
authors.forename: M P H M
authors.initials: MP
authors.lastname: Jansen
authors.forename: E A
authors.initials: EA
authors.lastname: Reijm
authors.forename: A M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: K
authors.initials: K
authors.lastname: Ruigrok-Ritstier
authors.forename: M P
authors.initials: MP
authors.lastname: Look
authors.forename: F G
authors.initials: FG
authors.lastname: Rodríguez-González
authors.forename: A A J
authors.initials: AA
authors.lastname: Heine
authors.forename: J W
authors.initials: JW
authors.lastname: Martens
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
authors.forename: J A
authors.initials: JA
authors.lastname: Foekens
authors.forename: E M J J
authors.initials: EM
authors.lastname: Berns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016203:CDC2 Protein Kinase; D019926:Cyclin B / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016203:CDC2 Protein Kinase; D019926:Cyclin B; D019927:Cyclin E; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D035683:MicroRNAs; D015513:Oncogene Proteins; D063151:Polycomb Repressive Complex 2; D013629:Tamoxifen; D014157:Transcription Factors; C475820:CCNE1 protein, human; C528163:MIRN26 microRNA, human; C498409:EZH2 protein, human; C528899:CDK1 protein, human
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