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2018-05-18

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cc-by (c) Ruiz de Garibay, Gorka et al., 2018
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/127027

Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance

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Recurs relacionat

https://doi.org/10.1242/dmm.032292

Resum

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 patientderived 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-mutaied 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.

Matèries

Càncer de mama, Quimioteràpia del càncer, Factors de transcripció, Resistència als medicaments, Cribratge

Matèries (anglès)

Breast cancer, Cancer chemotherapy, Transcription factors, Drug resistance, Medical screening

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

RUIZ DE GARIBAY, Gorka, MATEO GONZÁLEZ, Francesca, STRADELLA, Agostina, VALDÉS MAS, Rafael, PALOMERO, Luis, SERRA-MUSACH, Jordi, PUENTE, Diana a., DÍAZ-NAVARRO, Ander, VARGAS PARRA, Gardenía maría, TORNERO, Eva, MORILLA, Idoia, FARRÉ, Lourdes, MARTÍNEZ INIESTA, María, HERRANZ, Carmen, MCCORMACK, Emmet, VIDAL-BEL, August, PETIT, Anna, SOLER, María teresa, LÁZARO GARCÍA, Conxi, PUENTE, Xose s., VILLANUEVA GARATACHEA, Alberto, PUJANA GENESTAR, M. ángel. Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance. _Disease Models & Mechanisms_. 2018. Vol. 11, núm. 5, pàgs. dmm032292. [consulta: 20 de gener de 2026]. ISSN: 1754-8403. [Disponible a: https://hdl.handle.net/2445/127027]

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