title: BRCA1 mislocalization associated with breast carcinogenesis and poor prognosis in Taiwanese women.
abstract: We aimed to elucidate whether and how BRCA1 mislocalization [including membranous nuclear (MN) forms and negative patterns] is associated with the occurrence and the prognosis of breast cancer in young Taiwanese women. A case-control study was carried out to enroll 84 patients with breast cancer and 81 patients with benign breast disease. The subcellular localization of BRCA1 was examined using immunofluorescent assays on fresh tissue touch-imprinting slides to classify staining results into diffuse nuclear (DN), MN, and negative staining. Genetic variations of BRCA1 nuclear localization/transportation-related sequences were analyzed by cDNA sequencing of both nuclear localization signals (NLS) and nuclear export signals (NES). The BRCA1 antibody was verified by two other published ones. Comparisons of immunofluorescent assay with immunohistochemical and H&E staining methods were also performed. BRCA1 mislocalization conferred a 3.13-fold [95% confidence interval (CI): 1.31-7.50] risk of developing breast cancer for the MN form and a 5.79-fold (95% CI:1.58-21.23) risk for BRCA1-negative cases compared with DN staining. However, no genetic variant was found in the NES or the NLS region of the BRCA1 gene. In terms of prognosis, BRCA1 mislocalization showed a 3.5-fold (95% CI: 1.20-10.09) increased risk of breast cancer death compared with DN staining after adjusting for tumor node metastasis stage. BRCA1 MN forms and BRCA1-negative patterns led to a higher risk of carcinogenesis and a poor prognosis of breast cancer. Such BRCA1 mislocalization may not be directly caused by the genetic effects of the NLS and NES domains, but stem from nongenetic modifications (such as epigenetic silencing).
authors.affiliation: aGraduate Institute of Life Sciences bDepartment of Pathology, and Graduate Institute of Pathology and Parasitology, National Defense Medical Center Departments of cSurgery dPathology, Tri-Service General Hospital eSchool of Oral Hygiene, College of Oral Medicine, Taipei Medical University fGraduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei gDepartment of Obstetrics and Gynecology, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Jar-Yi
authors.initials: JY
authors.lastname: Ho
authors.forename: Ren-Jun
authors.initials: RJ
authors.lastname: Hsu
authors.forename: Chieh-Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Sheng-Hsien
authors.initials: SH
authors.lastname: Chen
authors.forename: Ming-Ye
authors.initials: MY
authors.lastname: Wu
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Gao
authors.forename: Amy Ming-Fang
authors.initials: AM
authors.lastname: Yen
authors.forename: Hsiu-Hsi
authors.initials: HH
authors.lastname: Chen
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D019913:Nuclear Localization Signals / Q000235:genetics*; D011379:Prognosis; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013624:Taiwan
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019913:Nuclear Localization Signals; D012333:RNA, Messenger