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

Palomeras, Sònia; Díaz‐Lagares, Ángel; Viñas, Gemma; Setién, Fernando; Ferreira, Humberto J.; Oliveras, Glòria; Crujeiras, Ana B.; Hernández, A.; Lum, David H.; Welm, Alana L.; Esteller, Manel; Puig, Teresa

doi:10.1186/s13058-019-1160-x

Cited by 50 publications

(34 citation statements)

References 59 publications

(72 reference statements)

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“…Moreover, it has been reported that TGFBI might be associated with Lapatinib resistance in HER2-positive breast cancer cell lines [253]. On the other hand, epigenetic silencing of TGFBI by DNA methylation has been found to contribute to the trastuzumab resistance in HER2-positive cell models [254]. Taken together, TGFBI can function as a chemo-sensitizer or a risk of chemo-resistance in various cancers.…”

Section: Transforming Growth Factor B Induced (Tgfbi) Protein and Brmentioning

confidence: 98%

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Song

Sinha

et al. 2019

Oncogene

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Section: Transforming Growth Factor B Induced (Tgfbi) Protein and Brmentioning

confidence: 98%

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Song

Sinha

et al. 2019

Oncogene

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“…TGFBI was also identi ed to be a hub gene strongly associated with oral squamous cell carcinoma and to be able to promote tumor metastasis [43] . In addition, the epigenetic silencing of TGFBI by DNA methylation can confer resistance to trastuzumab in breast cancer [44] . Furthermore, Wang et al [45] found the aberrant expression of TGFBI in RC.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in rectal cancer

Zhang¹,

Meng²,

Chao³

et al. 2020

Preprint

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BackgroundAbnormal hypomethylation of oncogenes and hypermethylation of tumor suppressor genes play important roles in human tumorigenesis and cancer progression, including those of rectal cancer (RC). However, conjoint analysis of RC involving both gene expression and methylation profiling datasets remains rare. This study aimed to identify methylation-regulated differentially expressed genes (MeDEGs) and to evaluate their prognostic value in RC through bioinformatics analysis.MethodsGene expression (GSE20842 and GSE68204) and gene methylation (GSE75546) profiling datasets were obtained from the Gene Expression Omnibus database. GEO2R was adopted to identify differentially expressed genes (DEGs) and differentially methylated genes (DMGs). MeDEGs were obtained by overlapping the DEGs and DMGs and then subjected to protein–protein interaction (PPI) network analysis using STRING. Modules and hub genes within the network were identified using MCODE and CytoHubba, respectively. Prognostic MeDEGs were selected by univariate Cox regression. Finally, our findings were validated based on The Cancer Genome Atlas (TCGA) database.ResultsIn total, 243 upregulated-hypomethylated and 51 downregulated-hypermethylated genes were identified as MeDEGs. A PPI network of MeDEGs was constructed with 290 nodes and 578 edges. Three modules and three hub genes—COL3A1, FPR1, and PLK1—within the network were identified. Three MeDEGs—NFE2, COMP, and LAMA1—were found to be survival-related. Furthermore, the expression and methylation status of two hub genes (excluding FPR1) and the three prognostic MeDEGs were also significantly altered in TCGA and were consistent with our findings.ConclusionsWe identified novel MeDEGs and explored their relationship with survival in RC. Our methodology may provide an effective bioinformatics basis for further understanding of the methylation-mediated regulatory mechanisms in RC.

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“…Palomeras et al reported that primary breast tumors that developed trastuzumab resistance present a loss of expression of transforming growth factor beta-induced protein (TGFBI) by hypermethylation. TGFBI inhibits the HER2 receptor and AKT (124). Abnormal activation of PI3K/AKT is common in breast cancer.…”

Section: Regulation Of the Pi3k/pten/akt/mtor Signaling Pathway By Dnmentioning

confidence: 99%

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

Romero-García¹,

Prado-Garcı́a²,

Carlos‐Reyes³

2020

Front. Oncol.

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Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.

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

Cited by 50 publications

References 59 publications

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Comprehensive analysis of DNA methylation and gene expression profiles in rectal cancer

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

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