title: Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer.
abstract: BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex, and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity, and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Ozden
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, 60612, U.S.A.
authors.forename: Faraz
authors.initials: F
authors.lastname: Bishehsari
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Jana
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sporn
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Jonas J
authors.initials: JJ
authors.lastname: Staudacher
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Cemal
authors.initials: C
authors.lastname: Yazici
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Nancy
authors.initials: N
authors.lastname: Krett
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059765:Homologous Recombination; D006801:Humans; D000077146:Irinotecan / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin / Q000494:pharmacology / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019154:Protein Splicing; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin; D000077146:Irinotecan; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases