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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 AT, Negm OH, Green AR, Nolan CC, Tighe P, Albarakati N, Sultana R, Madhusudan S, Ellis IO, Rakha EA - Br. J. Cancer (2015)

Bottom Line: 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<0.0001), but this effect was not independent of other prognostic variables.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK [2] Ministry of Higher Education, Riyadh, Saudi Arabia.

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 α-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, γH2AX, 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<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.

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Related in: MedlinePlus

Validation of KPNA2 primary antibody by western blotting. Mixed lysates from MCF7 and MDA-MB-436 cell lines were used.
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fig1: Validation of KPNA2 primary antibody by western blotting. Mixed lysates from MCF7 and MDA-MB-436 cell lines were used.

Mentions: The specificity of KPNA2 primary antibody was validated using western blotting as evident by a single band at the correct protein size (Figure 1). KPNA2 showed nuclear staining, which ranged from negative/weak to strong with no cytoplasmic or membranous staining observed (Figure 2). In sporadic BC, 51% (715 out of 1393) showed nuclear expression compared with 17 out of 19 cases (90%) of the hereditary BRCA1-mutated cases that showed KPNA2 expression (P<0.001).


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

Alshareeda AT, Negm OH, Green AR, Nolan CC, Tighe P, Albarakati N, Sultana R, Madhusudan S, Ellis IO, Rakha EA - Br. J. Cancer (2015)

Validation of KPNA2 primary antibody by western blotting. Mixed lysates from MCF7 and MDA-MB-436 cell lines were used.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4580386&req=5

fig1: Validation of KPNA2 primary antibody by western blotting. Mixed lysates from MCF7 and MDA-MB-436 cell lines were used.
Mentions: The specificity of KPNA2 primary antibody was validated using western blotting as evident by a single band at the correct protein size (Figure 1). KPNA2 showed nuclear staining, which ranged from negative/weak to strong with no cytoplasmic or membranous staining observed (Figure 2). In sporadic BC, 51% (715 out of 1393) showed nuclear expression compared with 17 out of 19 cases (90%) of the hereditary BRCA1-mutated cases that showed KPNA2 expression (P<0.001).

Bottom Line: 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<0.0001), but this effect was not independent of other prognostic variables.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK [2] Ministry of Higher Education, Riyadh, Saudi Arabia.

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 α-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, γH2AX, 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<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.

Show MeSH
Related in: MedlinePlus