title: Epigenetic Inactivation of BRCA1 Through Promoter Hypermethylation and Its Clinical Importance in Triple-Negative Breast Cancer.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases.
  
  
  METHODS
  Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry.
  
  
  RESULTS
  BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038).
  
  
  CONCLUSIONS
  BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Department of Comprehensive Clinical Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: eriko@surg2.med.kyushu-u.ac.jp.
authors.forename: Eriko
authors.initials: E
authors.lastname: Tokunaga
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitao
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Megan
authors.initials: M
authors.lastname: Hitchins
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hisamatsu
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Taketani
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Akiyoshi
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Anatomic Pathology, Pathological Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saeki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D012333:RNA, Messenger
keywords: BRCA1; Basal-like breast cancer; Breast cancer; Promotor methylation; Triple-negative breast cancer