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Title: Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance
Author: 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
Keywords: Càncer de mama
Quimioteràpia del càncer
Factors de transcripció
Resistència als medicaments
Breast cancer
Cancer chemotherapy
Transcription factors
Drug resistance
Medical screening
Issue Date: 18-May-2018
Publisher: The Company of Biologists
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Disease Models & Mechanisms, 2018, vol. 11, num. 5, p. dmm032292
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ISSN: 1754-8403
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

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