Abstract
BackgroundTargeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) is a microtubule associated protein that functions in mitotic spindle assembly. TPX2 also localizes to the nucleus where it functions in DNA damage repair during S-phase. We and others have previously shown that TPX2 RNA levels are strongly associated with chromosomal instability (CIN) in breast and other cancers, and TPX2 RNA levels have been demonstrated to correlate with aggressive behavior and poor clinical outcome across a range of solid malignancies, including breast cancer.MethodsWe perform TPX2 IHC on a cohort of 253 primary breast cancers and adopt a clinically amenable scoring system to separate tumors into low, intermediate, or high TPX2 expression. We then correlate TPX2 expression against diverse pathologic parameters and important measures of clinical outcome, including disease-specific and overall survival. We link TPX2 expression to TP53 mutation and evaluate whether TPX2 is an independent predictor of chromosomal instability (CIN).ResultsWe find that TPX2 nuclear expression strongly correlates with high grade morphology, elevated clinical stage, negative ER and PR status, and both disease-specific and overall survival. We also show that increased TPX2 nuclear expression correlates with elevated ploidy, supernumerary centrosomes, and TP53 mutation. TPX2 nuclear expression correlates with CIN via univariate analyses but is not independently predictive when compared to ploidy, Ki67, TP53 mutational status, centrosome number, and patient age.ConclusionsOur findings demonstrate a strong correlation between TPX2 nuclear expression and aggressive tumor behavior, and show that TPX2 overexpression frequently occurs in the setting of TP53 mutation and elevated ploidy. However, TPX2 expression is not an independent predictor of CIN where it fails to outperform existing clinical and pathologic metrics.
Highlights
Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) is a microtubule associated protein that functions in mitotic spindle assembly
Our findings demonstrate a strong correlation between TPX2 nuclear expression and aggressive tumor behavior, and show that TPX2 overexpression frequently occurs in the setting of TP53 mutation and elevated ploidy
We find that increased TPX2 nuclear expression is significantly associated with tumor grade, clinical stage, estrogen receptor (ER) status, progesterone receptor (PR) status, and both disease-specific and overall survival
Summary
Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) is a microtubule associated protein that functions in mitotic spindle assembly. Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) is a microtubule associated protein which critically regulates the formation of the mitotic spindle during mitosis, primarily by localizing and activating Aurora A kinase [1]. TPX2 enhances microtubule nucleation independent of Aurora A, assists in the targeting of mitotic kinesins to microtubule minus ends, and works in concert with Augmin to form microtubule branch points [2]. Together, these activities maintain genomic stability by ensuring the proper segregation of chromosomes during mitosis. TPX2 depletion results in an accumulation of cells in mitosis and it is required for the synthesis and phosphorylation of p53 in Xenopus oocytes [4,5,6,7]
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