Abstract 2557: X-ray repair cross complementing 1 (XRCC1) is a critical factor in response to DNA damaging agents in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is a breast cancer subtype that is characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The lack of these targetable molecules makes cytotoxic chemotherapies a first-line choice, thus there is a pressing need to better understand how TNBC will respond to alternative or emerging treatments. Base excision repair (BER) proteins play an essential role in DNA damage response and repair, yet they have been overlooked in the analysis of chemotherapeutic treatment response. XRCC1 is a critical scaffold protein that mediates the protein-protein and protein-DNA interactions involved in BER and single-strand break repair. Several studies have linked single nucleotide polymorphisms (SNPs) within XRCC1 to increases in breast cancer incidence, yet XRCC1’s role in modulating treatment response is unknown. Here we show XRCC1 expression in a panel of TNBC cell lines correlates to an increase in basal DNA damage levels. DNA damage was analyzed using the Repair Assisted Damage Detection (RADD) assay which measures the broadest spectrum of DNA damage in vitro. We show MDA-MB-157 with low levels of XRCC1 correlate to low levels of basal DNA damage, MDA-MB-231 and HCC1806 have moderate levels of XRCC1 and DNA damage, and MDA-MB-468 contain high expression levels of XRCC1 that correlate with high levels of DNA damage. XRCC1 localization is also variable across the panel of TNBC cell lines with XRCC1 being mislocalized to the cytoplasm in the HCC1806 cells and highly localized to the nuclear compartment in the MDA-MB-468. These expression and localization changes in XRCC1 alter the ability of cells to repair single strand break (SSB) lesions induced by 355 nM laser microirradiation and DNA damaging chemicals. Here we show that TNBC cell lines respond differently to alkylating damage (methyl methanesulfonate) and PARP inhibition (olaparib) based on XRCC1 expression and localization in combination with levels of basal DNA damage. Taken together it is important to consider XRCC1 in context with DNA damage levels and expression of other BER proteins in TNBC in order to effectively design experiments utilizing DNA damaging agents or chemotherapeutics targeting DNA repair pathways. Citation Format: Kevin J. Lee, Joel Andrews, Natalie R. Gassman. X-ray repair cross complementing 1 (XRCC1) is a critical factor in response to DNA damaging agents in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2557.