title: Targeting XRCC1 deficiency in breast cancer for personalized therapy.
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.
authors.affiliation: Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Rebeka
authors.initials: R
authors.lastname: Sultana
authors.forename: Tarek
authors.initials: T
authors.lastname: Abdel-Fatah
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbotts
authors.forename: Claire
authors.initials: C
authors.lastname: Hawkes
authors.forename: Nada
authors.initials: N
authors.lastname: Albarakati
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D006224:Cricetinae; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D058990:Molecular Targeted Therapy; D011379:Prognosis; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human