Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance
| Autor: | Ruiz de Garibay, Gorka, Mateo, Francesca, Stradella, Agostina, Valdés-Mas, Rafael, Palomero, Luis, Serra-Musach, Jordi, Puente, Diana A., Díaz-Navarro, Ander, Vargas-Parra, Gardenia, Tornero, Eva, Morilla, Idoia, Farré, Lourdes, Martinez-Iniesta, María, Herranz, Carmen, McCormack, Emmet, Vidal, August, Petit, Anna, Soler, Teresa, Lázaro, Conxi, Puente, Xose S., Villanueva, Alberto, Pujana, Miguel Angel |
|---|---|
| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Medical screening Resistance lcsh:Medicine Breast Neoplasms Càncer de mama Quimioteràpia del càncer Genetic Heterogeneity Mice Breast cancer Transcription Factor 4 Patient-derived xenograft Cell Line Tumor lcsh:Pathology Transcription factors Chemotherapy Animals Humans Resistència als medicaments TCF4 Base Sequence Xenograft lcsh:R Cell Cycle Prognosis Adaptation Physiological Xenograft Model Antitumor Assays Cribratge Drug Resistance Neoplasm Factors de transcripció Drug resistance Mutation Female Cancer chemotherapy Transcription factor lcsh:RB1-214 Research Article |
| Zdroj: | Disease Models & Mechanisms Recercat. Dipósit de la Recerca de Catalunya instname Disease Models & Mechanisms, Vol 11, Iss 5 (2018) Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutated PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance. Summary: By modeling chemoresistance in patient-derived breast cancer xenografts, this study shows that adaptation to therapy is genetically complex and that loss of transcription factor 4 (TCF4) is associated with this process. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|