Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer

Vaidyanathan, Srividya, Thangavelu, Pulari U. and Duijf, Pascal H. G. (2016) Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer. Targeted Oncology, 11 5: 1-10. doi:10.1007/s11523-016-0432-y


Author Vaidyanathan, Srividya
Thangavelu, Pulari U.
Duijf, Pascal H. G.
Title Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer
Journal name Targeted Oncology   Check publisher's open access policy
ISSN 1776-2596
1776-260X
Publication date 2016-03-29
Year available 2016
Sub-type Article (original research)
DOI 10.1007/s11523-016-0432-y
Open Access Status Not Open Access
Volume 11
Issue 5
Start page 1
End page 10
Total pages 10
Place of publication Paris, France
Publisher Springer-Verlag France
Language eng
Abstract Ran GTPase regulates nuclear import, nuclear export, and mitotic spindle assembly. The multifunctional involvement of seventeen Ran GTPase components in these processes has complicated research into how each contributes to cancer development.

To assess whether individual and process-specific misexpression of Ran GTPase components contribute to chromosome instability (CIN) and worsen breast cancer patient prognosis.

Using publicly available datasets, we studied the degree of misexpression of all Ran GTPase signaling components in breast cancer, assessed their involvement in CIN and used four clinical tests to evaluate whether their misregulation may constitute independent prognostic predictors.

A significant majority of Ran GTPase signaling components is overexpressed in breast cancer. Strikingly, spindle assembly components are overexpressed and associated with CIN with only marginal significance and four independent tests indicate that this does not worsen patient outcome. Overexpression of nuclear import components is neither CIN-associated nor clinically significant. In sharp contrast, overexpression of nuclear export components constitutes a strong independent marker for both CIN and poor patient prognosis. We identify Exportin 2/CSE1L, Exportin 3/XPOT, Exportin 5/XPO5, and RANBP1 as novel potential targets.

We find that overexpression of Ran GTPase components involved in nuclear export, but not nuclear import or mitotic spindle assembly, is a strong CIN-associated marker for poor breast cancer prognosis. This could mean that increased nuclear export (of, for instance, pRb, p53, p73, BRCA1, p21, p27, E2F4, IκB, survivin), rather than spindle defects, mainly drives CIN and tumorigenesis. Hence, selective inhibitors of nuclear export may be effective for treating the most aggressive and chromosomally unstable breast cancers.
Formatted abstract
Background:  Ran GTPase regulates nuclear import, nuclear export, and mitotic spindle assembly. The multifunctional involvement of seventeen Ran GTPase components in these processes has complicated research into how each contributes to cancer development.

Objective:  To assess whether individual and process-specific misexpression of Ran GTPase components contribute to chromosome instability (CIN) and worsen breast cancer patient prognosis.

Methods:  Using publicly available datasets, we studied the degree of misexpression of all Ran GTPase signaling components in breast cancer, assessed their involvement in CIN and used four clinical tests to evaluate whether their misregulation may constitute independent prognostic predictors.

Results:  A significant majority of Ran GTPase signaling components is overexpressed in breast cancer. Strikingly, spindle assembly components are overexpressed and associated with CIN with only marginal significance and four independent tests indicate that this does not worsen patient outcome. Overexpression of nuclear import components is neither CIN-associated nor clinically significant. In sharp contrast, overexpression of nuclear export components constitutes a strong independent marker for both CIN and poor patient prognosis. We identify Exportin 2/CSE1L, Exportin 3/XPOT, Exportin 5/XPO5, and RANBP1 as novel potential targets.

Conclusions:  We find that overexpression of Ran GTPase components involved in nuclear export, but not nuclear import or mitotic spindle assembly, is a strong CIN-associated marker for poor breast cancer prognosis. This could mean that increased nuclear export (of, for instance, pRb, p53, p73, BRCA1, p21, p27, E2F4, IκB, survivin), rather than spindle defects, mainly drives CIN and tumorigenesis. Hence, selective inhibitors of nuclear export may be effective for treating the most aggressive and chromosomally unstable breast cancers.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Created: Sun, 03 Apr 2016, 08:56:05 EST by Pascal Duijf on behalf of UQ Diamantina Institute