Integrative analysis of genomic amplification-dependent expression and loss-of-function screen identifies ASAP1 as a driver gene in triple-negative breast cancer progression
| Autor: | Marcel Smid, Bob van de Water, Sander Canisius, John A. Foekens, Ronan P. McLaughlin, John W.M. Martens, Yinghui Zhang, Lambert van der Beek, Lodewyk F. A. Wessels, Jichao He |
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| Přispěvatelé: | Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Candidate gene Triple Negative Breast Neoplasms Biology medicine.disease_cause Article Disease-Free Survival Metastasis 03 medical and health sciences Breast cancer 0302 clinical medicine SDG 3 - Good Health and Well-being Cell Line Tumor Gene duplication Cancer genomics Genetics medicine Humans Gene silencing Molecular Biology Triple-negative breast cancer Adaptor Proteins Signal Transducing Gene Amplification medicine.disease Neoplasm Proteins Survival Rate 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research Female Carcinogenesis |
| Zdroj: | Oncogene Oncogene, 39(20), 4118-4131 Oncogene, 39(20), 4118-4131. Nature Publishing Group |
| ISSN: | 0950-9232 |
| Popis: | The genetically heterogeneous triple-negative breast cancer (TNBC) continues to be an intractable disease, due to lack of effective targeted therapies. Gene amplification is a major event in tumorigenesis. Genes with amplification-dependent expression are being explored as therapeutic targets for cancer treatment. In this study, we have applied Analytical Multi-scale Identification of Recurring Events analysis and transcript quantification in the TNBC genome across 222 TNBC tumors and identified 138 candidate genes with positive correlation in copy number gain (CNG) and gene expression. siRNA-based loss-of-function screen of the candidate genes has validated EGFR, MYC, ASAP1, IRF2BP2, and CCT5 genes as drivers promoting proliferation in different TNBC cells. MYC, ASAP1, IRF2BP2, and CCT5 display frequent CNG and concurrent expression over 2173 breast cancer tumors (cBioPortal dataset). More frequently are MYC and ASAP1 amplified in TNBC tumors (>30%, n = 320). In particular, high expression of ASAP1, the ADP-ribosylation factor GTPase-activating protein, is significantly related to poor metastatic relapse-free survival of TNBC patients (n = 257, bc-GenExMiner). Furthermore, we have revealed that silencing of ASAP1 modulates numerous cytokine and apoptosis signaling components, such as IL1B, TRAF1, AIFM2, and MAP3K11 that are clinically relevant to survival outcomes of TNBC patients. ASAP1 has been reported to promote invasion and metastasis in various cancer cells. Our findings that ASAP1 is an amplification-dependent TNBC driver gene promoting TNBC cell proliferation, functioning upstream apoptosis components, and correlating to clinical outcomes of TNBC patients, support ASAP1 as a potential actionable target for TNBC treatment. |
| Databáze: | OpenAIRE |
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