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.
authors.affiliation: Department of Radiation Oncology, The Ohio State University College of Medicine, 072 A Starling Loving Hall, 300 W 10th Avenue, Columbus, OH 43212, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Santivasi
authors.affiliation: Department of Lung Cancer, The 307 Hospital of the People's Liberation Army, 8 East Street, Fengtai, Beijing, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Vanderbilt University School of Medicine, B1003 Preston Research Building, 1301 22nd Avenue South, Nashville, TN 37232, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Center for Biostatistics, The Ohio State University, 2012 Kenny Road, Room 244, Columbus, OH 43210, USA.
authors.forename: X
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: E
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Department of Radiation Oncology, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Haffty
authors.affiliation: Department of Radiation Oncology, Vanderbilt University School of Medicine, B1003 Preston Research Building, 1301 22nd Avenue South, Nashville, TN 37232, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Chakravarthy
authors.affiliation: Department of Radiation Oncology, The Ohio State University College of Medicine, 072 A Starling Loving Hall, 300 W 10th Avenue, Columbus, OH 43212, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Xia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015331:Cohort Studies; D003600:Cytosol / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D009362:Neoplasm Metastasis; D021381:Protein Transport; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor