Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
| Autor: | Hyun-Jung Kim, Lauren M. Zasadil, Beth A. Weaver, Ryan A. Denu, Robert F. Lera, Brittany Zachek, Jennifer Laffin, Josephine Harter, Kari B. Wisinski, Amber Lasek, Mark E. Burkard, Craig Kanugh, Sandeep Saha, Alka Choudhary |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Cell type Proline medicine.drug_class Karyotype Antineoplastic Agents Apoptosis Breast Neoplasms Kaplan-Meier Estimate Biology Antimetabolite Article Polyploidy 03 medical and health sciences Breast cancer Cell Line Tumor Drug Discovery medicine Benzoquinones Biomarkers Tumor Humans In Situ Hybridization Fluorescence Cell Proliferation Cell growth Topoisomerase Cancer Gene signature medicine.disease Prognosis Molecular biology Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Cancer research biology.protein Female Ploidy Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 15(1) |
| ISSN: | 1538-8514 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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