Abstract
XRCC1 is a key component of DNA base excision repair, single strand break repair, and backup nonhomologous end-joining pathway. XRCC1 (X-ray repair cross-complementing gene 1) deficiency promotes genomic instability, increases cancer risk, and may have clinical application in breast cancer. We investigated XRCC1 expression in early breast cancers (n = 1,297) and validated in an independent cohort of estrogen receptor (ER)-α-negative breast cancers (n = 281). Preclinically, we evaluated XRCC1-deficient and -proficient Chinese hamster and human cancer cells for synthetic lethality application using double-strand break (DSB) repair inhibitors [KU55933 (ataxia telangectasia-mutated; ATM inhibitor) and NU7441 (DNA-PKcs inhibitor)]. In breast cancer, loss of XRCC1 (16%) was associated with high grade (P < 0.0001), loss of hormone receptors (P < 0.0001), triple-negative (P < 0.0001), and basal-like phenotypes (P = 0.001). Loss of XRCC1 was associated with a two-fold increase in risk of death (P < 0.0001) and independently with poor outcome (P < 0.0001). Preclinically, KU55933 [2-(4-Morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one] and NU7441 [8-(4-Dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one] were synthetically lethal in XRCC1-deficient compared with proficient cells as evidenced by hypersensitivity to DSB repair inhibitors, accumulation of DNA DSBs, G2-M cell-cycle arrest, and induction of apoptosis. This is the first study to show that XRCC1 deficiency in breast cancer results in an aggressive phenotype and that XRCC1 deficiency could also be exploited for a novel synthetic lethality application using DSB repair inhibitors. Cancer Res; 73(5); 1621-34. ©2012 AACR.
Highlights
Impaired DNA repair is a driving force for carcinogenesis and may promote aggressive clinical behavior in breast cancer [1, 2]
Loss of XRCC1 expression was highly significantly associated with aggressive clinicopathologic features (Table 1) including high histologic grade (P < 0.0001), pleomorphism (P < 0.0001), glandular dedifferentiation (P 1⁄4 0.006), absence of hormonal receptors (ERÀ/PgRÀ/ARÀ; P < 0.0001), presence of basal-like phenotypes (P 1⁄4 0.001), and triple-negative phenotypes (P < 0.0001; Table 1)
XRCC1 is a key scaffolding protein intimately involved in Base excision repair (BER), SSB repair (SSBR), and back-up nonhomologous end-joining pathway (B-NHEJ)
Summary
Impaired DNA repair is a driving force for carcinogenesis and may promote aggressive clinical behavior in breast cancer [1, 2]. Base excision repair (BER) is required for the accurate removal of damaged DNA bases induced by oxidizing and alkylating agents. DNA single-strand breaks (SSB) induced by chemotherapeutics are processed by SSB repair (SSBR), a pathway related to BER. XRCC1 (X-ray repair cross-complementing gene 1) is a critical factor in BER, SSBR, and back-up nonhomologous end-joining pathway (B-NHEJ). Authors' Affiliations: 1Laboratory of Molecular Oncology, Academic Unit of Oncology; 2Division of Pathology; 3Academic Haematology, School of Molecular Medical Sciences, University of Nottingham; 4Department of Clinical Oncology, Nottingham University Hospitals; and 5School of Science and Technology, Nottingham Trent University, Clifton campus, Nottingham, United Kingdom. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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