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.