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Title: Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer
Author: Palomeras, Sonia
Diaz-Lagares, Angel
Viñas, Gemma
Setién, Fernando
Ferreira, Humberto J.
Oliveras Serrat, Glòria
Crujeiras, Ana B.
Hernández, Alejandro
Lum, David H.
Welm, Alana
Esteller, Manel
Puig i Miquel, Teresa
Keywords: Medicaments antineoplàstics
Resistència als medicaments
Matriu extracel·lular
Factors de creixement
Antineoplastic agents
Drug resistance
Extracellular matrix
Growth factors
Issue Date: 5-Jul-2019
Publisher: BioMed Central
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Breast Cancer Research, 2019, vol. 21, num. 1, p. 79
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ISSN: 1465-5411
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Fisiològiques)

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