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Integrative analysis of genomic amplification-dependent expression and loss-of-function screen identifies ASAP1 as a driver gene in triple-negative breast cancer progression.
He, Jichao; McLaughlin, Ronan P; van der Beek, Lambert; Canisius, Sander; Wessels, Lodewyk; Smid, Marcel; Martens, John W M; Foekens, John A; Zhang, Yinghui; van de Water, Bob.
Afiliación
  • He J; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
  • McLaughlin RP; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
  • van der Beek L; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
  • Canisius S; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
  • Wessels L; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
  • Smid M; Department of Medical Oncology and Cancer Genomic Netherlands, Erasmus MC Cancer Institute, Erasmus Medical Centre, 3000 CA, Rotterdam, The Netherlands.
  • Martens JWM; Department of Medical Oncology and Cancer Genomic Netherlands, Erasmus MC Cancer Institute, Erasmus Medical Centre, 3000 CA, Rotterdam, The Netherlands.
  • Foekens JA; Department of Medical Oncology and Cancer Genomic Netherlands, Erasmus MC Cancer Institute, Erasmus Medical Centre, 3000 CA, Rotterdam, The Netherlands.
  • Zhang Y; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
  • van de Water B; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands. b.water@lacdr.leidenuniv.nl.
Oncogene ; 39(20): 4118-4131, 2020 05.
Article en En | MEDLINE | ID: mdl-32235890
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amplificación de Genes / Proteínas Adaptadoras Transductoras de Señales / Neoplasias de la Mama Triple Negativas / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amplificación de Genes / Proteínas Adaptadoras Transductoras de Señales / Neoplasias de la Mama Triple Negativas / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido