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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.    Electronic supplementary material  The online version of this article (10.1186/s13058-019-1160-x) contains supplementary material, which is available to authorized users.

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