title: Co-treatment with BEZ235 Enhances Sensitivity of BRCA1-negative Breast Cancer Cells to Olaparib.
abstract: The poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib has been reported as having preferential anti-proliferative effects on breast cancer 1 (BRCA1)-deficient breast and ovarian cancer cells and was recently approved by the US Food and Drug Administration (FDA) for advanced, BRCA1-mutated ovarian cancer. Herein, we show that BEZ235, a protein kinase inhibitor, enhanced the tumor cell-killing effect of olaparib in BRCA1-mutated breast cancer cells in vitro. BEZ235 reduced olaparib-induced phosphorylation of p53 binding protein 1 (53BP1) and 53BP1 foci formation, as well as phosphorylation of AKT (S473). Long-term colony-formation assay revealed more strong synergistic effects of this combination in SUM149PT and MDA-MB-468 breast cancer cell lines. BEZ235 treatment combined with olaparib may be a candidate for effective therapeutic treatment of BRCA1-mutated breast cancer.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, U.S.A. Department of Nanobiomedical Science & BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.affiliation: Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Jeong-Soo
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Sahng-June
authors.initials: SJ
authors.lastname: Kwak
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, U.S.A. Department of Nanobiomedical Science & BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea seongys@dankook.ac.kr.
authors.forename: Yeon-Sun
authors.initials: YS
authors.lastname: Seong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010793:Phthalazines; D010879:Piperazines; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071857:Tumor Suppressor p53-Binding Protein 1; C498301:TP53BP1 protein, human; C531198:dactolisib; C531550:olaparib
keywords: 53BP1; BEZ235; BRCA1; Olaparib; breast cancer