Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Isabel F Fernández,Marta Sanz-García,Pedro A Lazo,Sandra Blanco,Marcella Salzano,Marta Vázquez-Cedeira,Alberto Valbuena

doi:10.18632/oncotarget.1678

Abstract

Vaccinia-related kinase 1 (VRK1) belongs to a group of sixteen kinases associated to a poorer prognosis in human breast carcinomas, particularly in estrogen receptor positive cases based on gene expression arrays. In this work we have studied the potential molecular mechanism by which the VRK1 protein can contribute to a poorer prognosis in this disease. For this aim it was first analyzed by immunohistochemistry the VRK1 protein level in normal breast and in one hundred and thirty six cases of human breast cancer. The effect of VRK1 to protect against DNA damage was determined by studying the effect of its knockdown on the formation of DNA repair foci assembled on 53BP1 in response to treatment with ionizing radiation or doxorubicin in two breast cancer cell lines. VRK1 protein was detected in normal breast and in breast carcinomas at high levels in ER and PR positive tumors. VRK1 protein level was significantly lower in ERBB2 positive cases. Next, to identify a mechanism that can link VRK1 to poorer prognosis, VRK1 was knocked-down in two breast cancer cell lines that were treated with ionizing radiation or doxorubicin, both inducing DNA damage. Loss of VRK1 resulted in reduced formation of DNA-damage repair foci complexes assembled on the 53BP1 scaffold protein, and this effect was independent of damaging agent or cell type. This observation is consistent with detection of high VRK1 protein levels in ER and PR positive breast cancers. We conclude that VRK1 can contribute to make these tumors more resistant to DNA damage-based therapies, such as ionizing radiation or doxorubicin, which is consistent with its association to a poor prognosis in ER positive breast cancer. VRK1 is potential target kinase for development of new specific inhibitors which can facilitate sensitization to other treatments in combination therapies; or alternatively be used as a new cancer drugs.

Highlights

Breast cancer represents one of the most frequent tumors in humans, and despite a significant improvement in survival resulting from an earlier diagnosis and new therapies; it still represents a major medical problem
The analysis of the human kinome in breast cancer cases led to the identification of a gene expression signature containing sixteen kinases that was associated with a poorer prognosis, and Vaccinia-related kinase 1 (VRK1) was present in this group [6]
Receptor positive breast cancer has high levels of VRK1, a situation that has been reported in other tumors such as head and neck squamous cell carcinomas [23], non-small lung cancer [24] and high-grade astrocytomas [25]

Summary

Introduction

Breast cancer represents one of the most frequent tumors in humans, and despite a significant improvement in survival resulting from an earlier diagnosis and new therapies; it still represents a major medical problem. In human breast cancer the analysis of gene expression has led to the identification of several kinases as potential prognostic markers [3, 4] These studies identified the VRK1 kinase as a marker for a subgroup with a poorer prognosis within the estrogen receptor positive cases. The analysis of the human kinome in breast cancer cases led to the identification of a gene expression signature containing sixteen kinases that was associated with a poorer prognosis, and VRK1 was present in this group [6] This association was mainly detected in luminal tumors, suggesting their potential use as marker or therapeutic targets in this subgroup of breast cancers [6]

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Results

Conclusion