title: Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers.
abstract: BACKGROUND
  Ribonucleotide reductase (RR) is an essential enzyme involved in DNA synthesis. We hypothesized that RR subunit M2 (RRM2) might be a novel prognostic and predictive biomarker for estrogen receptor (ER)-negative breast cancers.
  
  
  METHODS
  Individual and pooled survival analyses were conducted on six independent large-scale breast cancer microarray data sets; and findings were validated on a human breast tissue set (ZJU set).
  
  
  RESULTS
  Gene set enrichment analysis revealed that RRM2-high breast cancers were significantly enriched for expression of gene sets that increased in proliferation, invasiveness, undifferentiation, embryonic stem/progenitor-like phenotypes, and poor patient survival (p < 0.01). Independent and pooled analyses verified that increased RRM2 mRNA levels were associated with poor patient outcome in a dose-dependent manner. The prognostic power of RRM2 mRNA was comparable to multiple gene signatures, and it was superior to TNM stage. In ER-negative breast cancers, RRM2 showed more prognostic power than that in ER-positive breast cancers. Further analysis indicated that RRM2 was a more accurate prognostic biomarker for ER-negative breast cancers than the pathoclinical indicators and uPA. A new RR inhibitor, COH29, could significantly enhance the chemosensitivity to doxorubicin in ER-negative MDA-MB-231 cells, but not in ER-positive MCF-7 cells.
  
  
  CONCLUSIONS
  RRM2 appears to be a promising prognostic biomarker and therapeutic target for ER-negative breast cancer patients.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.forename: Charles D
authors.initials: CD
authors.lastname: Warden
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Sofia
authors.initials: S
authors.lastname: Loera
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.forename: Suzhan
authors.initials: S
authors.lastname: Zhang
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China. zhengshu@zju.edu.cn.
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D004317:Doxorubicin; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase