title: Protein expression and methylation of DNA repair genes hMLH1, hMSH2, MGMT and BRCA1 and their correlation with clinicopathological parameters and prognosis in basal-like breast cancer.
abstract: OBJECTIVE
  Basal-like breast cancer (BLBC) is characterized by aggressive behaviour; its genesis is the perturbation of DNA repair as a consequence of BRCA1 methylation or mutation. We comparatively evaluated alterations of DNA repair proteins and p53 between BLBC and non-BLBC cases.
  
  
  RESULTS
  Tumour sections from 104 BLBC and 89 non-BLBC patients were immunostained for hMLH1, hMSH2, MGMT, BRCA1 and p53. Methylation status of DNA repair genes was analysed by methylation-specific PCR, and p53 mutation was examined by direct sequencing. Immunoreactive levels of hMLH1 and MGMT were lower in BLBC, whereas the levels of hMSH2 and p53 were higher, compared to non-BLBC (P ≤ 0.014). Reduced expression of hMLH1 [hazard ratio (HR) 5.26, P = 0.001] and preserved expression of MGMT (HR 2.58, P = 0.039) proved to be independent predictors of poor survival in BLBC patients. DNA repair genes were methylated in approximately 20-40% of BLBCs without a significant relationship between their methylation and p53 mutation. BRCA1 methylation was associated with the loss of its protein expression (P = 0.004). MGMT methylation was linked to larger tumour size (P < 0.001).
  
  
  CONCLUSIONS
  Perturbations of the DNA repair system might be different between BLBC and non-BLBC. Alterations of hMLH1 and MGMT appear important for tumour progression and survival in BLBC patients.
authors.affiliation: Department of Breast Oncology, Juntendo University School of Medicine, Tokyo, Japan; Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yimit
authors.initials: Y
authors.lastname: Alkam
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakai
authors.forename: Takanori
authors.initials: T
authors.lastname: Himuro
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Michiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Arakawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.forename: Mitsue
authors.initials: M
authors.lastname: Saito
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: DNA repair gene; basal-like subtype; breast cancer; p53; promoter methylation