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KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer

Alshareeda, A.T.; Negm, O.H.; Green, A.R.; Nolan, C.C.; Tighe, P.; Albarakati, N.; Sultana, R.; Madhusudan, S.; Ellis, I.O.; Rakha, E.A.

Authors

A.T. Alshareeda

OLA NEGM ola.negm@nottingham.ac.uk
Assistant Professor

C.C. Nolan

PATRICK TIGHE paddy.tighe@nottingham.ac.uk
Professor of Molecular Immunology

N. Albarakati

R. Sultana

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology



Abstract

Background: It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin a-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC.
Methods: A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry.
Results: KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, gammaH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P less than 0.0001), but this effect was not independent of other prognostic variables.
Conclusions: This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.

Citation

Alshareeda, A., Negm, O., Green, A., Nolan, C., Tighe, P., Albarakati, N., …Rakha, E. (2015). KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer. British Journal of Cancer, 112(12), 1929–1937. https://doi.org/10.1038/bjc.2015.165

Journal Article Type Article
Acceptance Date Mar 31, 2015
Online Publication Date May 19, 2015
Publication Date Jun 9, 2015
Deposit Date May 29, 2018
Publicly Available Date Mar 29, 2024
Print ISSN 0007-0920
Publisher Cancer Research UK
Peer Reviewed Peer Reviewed
Volume 112
Issue 12
Pages 1929–1937
DOI https://doi.org/10.1038/bjc.2015.165
Public URL http://www.ncbi.nlm.nih.gov/pubmed/25989275
Publisher URL https://www.nature.com/articles/bjc2015165