Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer.

Kevin J Lee,Cortt G Piett,Joel F Andrews,Elise Mann,Natalie R Gassman,Zachary D Nagel,Malka Cohen-Armon

doi:10.1371/journal.pone.0223725

Abstract

DNA repair defects have been increasingly focused on as therapeutic targets. In hormone-positive breast cancer, XRCC1-deficient tumors have been identified and proposed as targets for combination therapies that damage DNA and inhibit DNA repair pathways. XRCC1 is a scaffold protein that functions in base excision repair (BER) by mediating essential interactions between DNA glycosylases, AP endonuclease, poly(ADP-ribose) polymerase 1, DNA polymerase β (POL β), and DNA ligases. Loss of XRCC1 confers BER defects and hypersensitivity to DNA damaging agents. BER defects have not been evaluated in triple negative breast cancers (TNBC), for which new therapeutic targets and therapies are needed. To evaluate the potential of XRCC1 as an indicator of BER defects in TNBC, we examined XRCC1 expression in the TCGA database and its expression and localization in TNBC cell lines. The TCGA database revealed high XRCC1 expression in TNBC tumors and TNBC cell lines show variable, but mostly high expression of XRCC1. XRCC1 localized outside of the nucleus in some TNBC cell lines, altering their ability to repair base lesions and single-strand breaks. Subcellular localization of POL β also varied and did not correlate with XRCC1 localization. Basal levels of DNA damage correlated with observed changes in XRCC1 expression, localization, and measure repair capacity. The results confirmed that XRCC1 expression changes indicate DNA repair capacity changes but emphasize that basal DNA damage levels along with protein localization are better indicators of DNA repair defects. Given the observed over-expression of XRCC1 in TNBC preclinical models and tumors, XRCC1 expression levels should be assessed when evaluating treatment responses of TNBC preclinical model cells.

Highlights

Defects in DNA damage response and repair are driving factors in carcinogenesis and key determinants for chemotherapeutic response
Despite previous publications indicating a loss in X-ray cross complementing protein 1 (XRCC1) to be an important indicator for triple negative breast cancers (TNBC) [16], XRCC1 transcript expression levels were significantly higher in primary tumor samples than in normal tissues with a p value of 1.6 x 10−12 (Primary tumor to Normal)(Fig 1A)
Little is known about base excision repair (BER) defects in breast cancer, those linked to XRCC1

Summary

Introduction

Defects in DNA damage response and repair are driving factors in carcinogenesis and key determinants for chemotherapeutic response. Breast cancers may display defects in DNA repair such as mutations in key DNA damage response and repair proteins such as breast cancer-susceptibility gene (BRCA1/2) and tumor suppressor protein p53 (TP53), and altered. Defective BER in triple negative breast cancer. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion