title: Increased ID4 expression, accompanied by mutant p53 accumulation and loss of BRCA1/2 proteins in triple-negative breast cancer, adversely affects survival.
abstract: OBJECTIVE
  Breast cancer 1 (BRCA1) expression is down-regulated in a significant proportion of non-hereditary breast cancers, in the absence of any mutation. This phenomenon is more pronounced in oestrogen (ER)-negative tumours. Recent studies have suggested that inhibitor of DNA binding 4 (ID4), as well as p53, participate in the transcriptional regulation of BRCA1.
  
  
  METHODS
  Immunohistochemical expression of ID4, BRCA1, BRCA2 and p53 in 699 women with triple-negative breast cancer was investigated using tissue microarrays. The prognostic role of these biomarkers was also evaluated. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics.
  
  
  RESULTS
  Loss of BRCA1 and BRCA2 expression and overexpression of ID4 and p53 was observed in 75%, 90%, 95% and 66% of tumours, respectively. ID4 expression was increased in higher tumour grade (P < 0.001) and was associated significantly with basal-like subtype (P < 0.001), BRCA2 down-regulation (P = 0.037) and p53 accumulation (P < 0.001). Patients with strong ID4 expression displayed worse disease-free survival in both triple-negative breast cancers (P = 0.041) and basal-like triple-negative breast cancers (P = 0.026).
  
  
  CONCLUSIONS
  There is frequent ID4 expression and concomitant loss of BRCA proteins in triple-negative breast cancer. We hypothesize that strong ID4 expression could be useful as a prognostic marker in triple-negative breast cancer, predicting early tumour recurrence.
authors.affiliation: Department of Pathology, Singapore General Hospital, Academia, Singapore, Singapore.
authors.forename: Aye A
authors.initials: AA
authors.lastname: Thike
authors.affiliation: Department of Pathology, Singapore General Hospital, Academia, Singapore, Singapore.
authors.forename: Puay H
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Department of Pathology, Singapore General Hospital, Academia, Singapore, Singapore.
authors.forename: Murasaki
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Pathology, Singapore General Hospital, Academia, Singapore, Singapore.
authors.forename: Jabed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012846:Singapore; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D016159:Tumor Suppressor Protein p53
keywords: BRCA1; BRCA2; ID4; immunohistochemistry; p53; triple negative breast cancer