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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Authors: Sònia Palomeras, Ángel Diaz-Lagares, Gemma Viñas, Fernando Setien, Humberto J. Ferreira, Glòria Oliveras, Ana B. Crujeiras, Alejandro Hernández, David H. Lum, Alana L. Welm, Manel Esteller, Teresa Puig

Published in: Breast Cancer Research | Issue 1/2019

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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.
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Metadata
Title
Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer
Authors
Sònia Palomeras
Ángel Diaz-Lagares
Gemma Viñas
Fernando Setien
Humberto J. Ferreira
Glòria Oliveras
Ana B. Crujeiras
Alejandro Hernández
David H. Lum
Alana L. Welm
Manel Esteller
Teresa Puig
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1160-x

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