Abstract 2144: STAT3 regulates the expression of XRCC1 in triple negative breast cancer

Abstract

Abstract Background: Base excision repair (BER) addresses base lesions and abasic sites induced by endogenous and exogenous environmental stresses. XRCC1 is a scaffold protein that facilitates and coordinates the BER repair machinery. Alterations in the protein and gene expression of XRCC1 have been observed in a multitude of cancers, including triple negative breast cancers (TNBC). Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. However, only two transcription factors, E2F1 and Sp1 have been implicated in the transcriptional regulation of XRCC1 to date. Methods: Utilizing promoter luciferase, transcription factor promoter binding ELISA, and chromatin immunoprecipitation (CHiP), STAT3 binding was identified and mapped in the XRCC1 promoter. Results: In the current study, we identify a STAT3 binding site within the XRCC1 promoter. Importantly, STAT3 regulation of XRCC1 appears to be constitutive in TNBC cell line models where STAT3 is highly activated. In HEK293T cells, the STAT3 binding site shows low occupancy under basal growth condition, but STAT3 regulation of XRCC1 can be stimulated by cytokine or mitogenic signaling by IL-6 and epidermal growth factor (EGF). Summary: STAT3 conditionally regulates XRCC1 under specific stress conditions to promote BER. In TNBC, the overexpression of XRCC1 by activated STAT3 likely contributes to increased resistance to DNA damaging chemotherapeutics. Citation Format: Griffin M. Wright, Natalie R. Gassman. STAT3 regulates the expression of XRCC1 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2144.