Tumor xenograft modeling identifies TCF4/ITF2 loss associated with breast cancer chemoresistance
| Autor: | Alberto Villanueva, Miguel Angel Pujana, Conxi Lázaro, María Martínez-Iniesta, August Vidal, Gardenia Vargas-Parra, Idoia Morilla, Luis Palomero, Agostina Stradella, Anna Petit, Jordi Serra-Musach, Diana A. Puente, Eva Tornero, Teresa Soler, Gorka Ruiz de Garibay, Carmen Herranz, Francesca Mateo, Xose S. Puente, Lourdes Farre, Rafael Valdés-Mas, Ander Diaz-Navarro, Emmet McCormack |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Somatic cell Neuroscience (miscellaneous) Medicine (miscellaneous) TCF4 Cell cycle Biology medicine.disease General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Breast cancer Immunology and Microbiology (miscellaneous) 030220 oncology & carcinogenesis Expression quantitative trait loci medicine Cancer research Gene Transcription factor Exome sequencing |
| Zdroj: | Disease Models & Mechanisms. |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.032292 |
| 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. |
| Databáze: | OpenAIRE |
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