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| Página principal > Artículos > Artículos publicados > Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer |
(Complejo Hospitalario Universitario de Santiago de Compostela) (Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitat de Girona. Departament de Ciències Mèdiques)| Fecha: | 2019 |
| Resumen: | Background: Acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: We performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: Epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: Our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients. |
| Ayudas: | Instituto de Salud Carlos III PI11-00692 Instituto de Salud Carlos III PI14-00329 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR00385 Instituto de Salud Carlos III JR17-00016 Instituto de Salud Carlos III CP17-00088 |
| Nota: | Altres ajuts: This work was supported in part by La Marató de TV3 (20131530, TPuig), financial support was from the University of Girona (MPCUdG2016/036), and the University of Girona and La Caixa Foundation awarded S. Palomeras with a predoctoral grant. |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | DNA methylation ; HER2+ breast cancer ; TGFBI ; Trastuzumab resistance |
| Publicado en: | Breast cancer research, Vol. 21 Núm. 1 (may 2019) , p. 79, ISSN 1465-542X |
