Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer Journal Article


Authors: Santivasi, W. L.; Wang, H.; Wang, T.; Yang, Q.; Mo, X.; Brogi, E.; Haffty, B. G.; Chakravarthy, A. B.; Xia, F.
Article Title: Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer
Abstract: Background: Although BRCA1 has been extensively studied for its role as a tumour-suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer.Methods: Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion.Results: An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2-14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency.Conclusions: Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease. © 2015 Cancer Research UK. All rights reserved.
Keywords: adult; cancer survival; controlled study; human tissue; human cell; major clinical study; cancer risk; cancer patient; cancer staging; outcome assessment; breast cancer; gene expression; cohort analysis; genetic association; in vitro study; brca1 protein; lung metastasis; cell culture; cancer cell; clinical evaluation; cell migration; tissue microarray; cell invasion; cytosol; correlational study; metastasis free survival; human; priority journal; article
Journal Title: British Journal of Cancer
Volume: 113
Issue: 3
ISSN: 0007-0920
Publisher: Nature Publishing Group  
Date Published: 2015-07-28
Start Page: 453
End Page: 459
Language: English
DOI: 10.1038/bjc.2015.208
PROVIDER: scopus
PMCID: PMC4522623
PUBMED: 26057449
DOI/URL:
Notes: Export Date: 2 September 2015 -- Source: Scopus
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  1. Edi Brogi
    515 Brogi