Research Papers: Breast CancerBRCA1 mislocalization associated with breast carcinogenesis and poor prognosis in Taiwanese womenHo, Jar-Yia,*; Hsu, Ren-Junb,*; Wu, Chieh-Linb,*; Chen, Sheng-Hsieng; Wu, Ming-Yeb; Yu, Jyh-Cherngc; Gao, Hong-Weid; Yen, Amy Ming-Fange; Chen, Hsiu-Hsif; Yu, Cheng-PingbAuthor Information 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 * Jar-Yi Ho, Ren-Jun Hsu and Chieh-Lin Wu contributed equally to the writing of this article. Correspondence to Cheng-Ping Yu, PhD, Department of Pathology, Tri-Service General Hospital, 114 No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei City 114, Taiwan Tel: +886 2 87923311 x12325; fax: +886 2 6600 0309; e-mail: [email protected] Received May 22, 2013 Accepted November 11, 2014 European Journal of Cancer Prevention: September 2015 - Volume 24 - Issue 5 - p 407-415 doi: 10.1097/CEJ.0000000000000114 Buy Metrics 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). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.