BRCA1 mislocalization associated with breast carcinogenesis and poor prognosis in Taiwanese women

Jar Yi Ho, Ren Jun Hsu, Chieh Lin Wu, Sheng Hsien Chen, Ming Ye Wu, Jyh Cherng Yu, Hong Wei Gao, Amy Ming Fang Yen, Hsiu Hsi Chen, Cheng Ping Yu

Research output: Contribution to journalArticle

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).

Original languageEnglish
Pages (from-to)407-415
Number of pages9
JournalEuropean Journal of Cancer Prevention
Volume24
Issue number5
DOIs
Publication statusPublished - Aug 8 2015

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Keywords

  • BRCA1
  • breast cancer
  • carcinogenesis
  • mislocalization
  • prognosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Epidemiology
  • Public Health, Environmental and Occupational Health

Cite this

Ho, J. Y., Hsu, R. J., Wu, C. L., Chen, S. H., Wu, M. Y., Yu, J. C., Gao, H. W., Yen, A. M. F., Chen, H. H., & Yu, C. P. (2015). BRCA1 mislocalization associated with breast carcinogenesis and poor prognosis in Taiwanese women. European Journal of Cancer Prevention, 24(5), 407-415. https://doi.org/10.1097/CEJ.0000000000000114