The Sub-Cellular Localization of WRAP53 Has Prognostic Impact in Breast Cancer.

Laxmi Silwal-Pandit,Bjørn Naume,Anita Langerød,Veronica Skarpeteig,Rolf Kåresen,Ellen Schlichting,Marianne Farnebo,Hans Kristian Moen Vollan,Hege Russnes,Elin Borgen,Anne-Lise Børresen-Dale,William B Coleman

doi:10.1371/journal.pone.0139965

Laxmi Silwal-Pandit, Bjørn Naume + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0139965

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Abstract

WRAP53 protein controls intracellular trafficking of DNA repair proteins, the telomerase enzyme, and splicing factors. Functional loss of the protein has been linked to carcinogenesis, premature aging and neurodegeneration. The aim of this study was to investigate the prognostic significance of WRAP53 protein expression in breast cancer. A tissue microarray was constructed from primary breast tumors and immunostained by a polyclonal WRAP53 antibody to assess the protein expression pattern. Two different patient cohorts with long term follow-up were studied; a test- and a validation set of 154 and 668 breast tumor samples respectively. Breast cancer patients with tumor cells lacking the expression of WRAP53 in the nucleus had a significantly poorer outcome compared to patients with tumor cells expressing this protein in the nuclei (HR = 1.95, 95%CI = 1.09–3.51, p = 0.025). Nuclear localization of WRAP53 was further shown to be an independent marker of prognosis in multivariate analysis (HR = 2.57, 95%CI = 1.27–5.19, p = 0.008), and also significantly associated with better outcome in patients with TP53 mutation. Here we show that the sub-cellular localization of the WRAP53 protein has a significant impact on breast cancer survival, and thus has a potential as a clinical marker in diagnostics and treatment.

Highlights

The WRAP53 protein is encoded by the WRAP53 gene, which has a genomic location in headto-head arrangement with the TP53 gene on 17p13.1[1]
The WRAP53 protein has been reported to be overexpressed in a broad range of cancer cell lines compared to non transformed cells[13], as well as in primary rectal tumor cells compared to normal mucosal cells[12]
Increased expression of WRAP53 was observed in esophageal squamous cell carcinoma tissue compared to adjacent non-neoplastic esophageal mucosa tissue[11]

Summary

Introduction

The WRAP53 protein is encoded by the WRAP53 gene, which has a genomic location in headto-head arrangement with the TP53 gene on 17p13.1[1]. The protein WRAP53 (alias WRAP53β TCAB1 and WDR79) is 75kDa, consists of 548 amino acids and contains a highly conserved WD40 repeat domain. WRAP53 facilitates interactions of factors involved in splicing and telomere elongation and their assembly in nuclear organelles termed Cajal bodies[2,3,4].Depletion of PLOS ONE | DOI:10.1371/journal.pone.0139965. WRAP53 interferes with the localization of telomerase in Cajal bodies and disrupts telomerasetelomere association, interfering with telomere synthesis and resulting in telomere shortening [2]. WRAP53 is an essential component of Cajal bodies and loss of this protein, or its aberrant overexpression, leads to collapse of these organelles and mislocalization of associated factors[3,4]. Recent findings demonstrate that the WRAP53 protein is a regulator of DNA double-strand break repair by providing a scaffold for DNA repair proteins[5]

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