title: Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer.
abstract: Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48-59. ©2015 AACR.
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Alka
authors.initials: A
authors.lastname: Choudhary
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Brittany
authors.initials: B
authors.lastname: Zachek
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lera
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Zasadil
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Amber
authors.initials: A
authors.lastname: Lasek
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Denu
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, Wisconsin.
authors.forename: Craig
authors.initials: C
authors.lastname: Kanugh
authors.affiliation: Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, Wisconsin. Department of Pediatrics, University of Wisconsin, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Laffin
authors.affiliation: Department of Pathology, University of Wisconsin, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Harter
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Kari B
authors.initials: KB
authors.lastname: Wisinski
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saha
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Weaver
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin. Hematology/Oncology Division, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. mburkard@wisc.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burkard
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D059785:Karyotype; D011123:Polyploidy; D011379:Prognosis; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C576309:2,5-di-(N-prolyl)-para-benzoquinone; D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D011392:Proline