Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R

Autor: Angang Yang, Lin-Tao Jia, Ying Chen, Ting Wang, Lei Wang, Xing-Ming Ye, Huayu Zhu, Wen-Dong Bai
Jazyk: angličtina
Předmět:
Cancer Research
Receptor
ErbB-2
medicine.medical_treatment
Targeted therapy
miR-375
Epigenesis
Genetic
Receptor
IGF Type 1
Mice
Phosphatidylinositol 3-Kinases
Breast cancer
Trastuzumab
Insulin-like growth factor 1 receptor
Trastuzumab resistance
skin and connective tissue diseases
Gene Expression Regulation
Neoplastic
Oncology
DNA methylation
erbB2/HER2
Female
medicine.drug
Research Article
Signal Transduction
Cell Survival
Antineoplastic Agents
Breast Neoplasms
Biology
Antibodies
Monoclonal
Humanized
Growth factor receptor
Cell Line
Tumor
microRNA
medicine
Genetics
Gene silencing
Animals
Humans
Gene Silencing
neoplasms
Cell Proliferation
Gene Expression Profiling
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
MicroRNAs
Drug Resistance
Neoplasm
Immunology
Cancer research
Proto-Oncogene Proteins c-akt
Zdroj: BMC Cancer
ISSN: 1471-2407
DOI: 10.1186/1471-2407-14-134
Popis: Background Resistance to humanized monoclonal erbB2/HER2 antibody, trastuzumab (Herceptin), has become a pivotal obstacle for targeted therapy of HER2-positive breast cancers. The activation of alternative growth factor receptors, in particular, the insulin-like growth factor 1 receptor (IGF1R), represents a common feature of trastuzumab-refractory cells; however, the underlying mechanism remains elusive. Methods Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3 cells in the presence of trastuzumab. Among the differentially expressed microRNAs (miRNAs) screened by microarray analysis, candidate miRNA(s) predicted to target IGF1R was studied for its role in conferring trastuzumab resistance. The mechanism underlying decreased expression of IGF1R-targeted miRNA in refractory cells was also addressed. Results miR-375, which was downregulated and predicted to target IGF1R in trastuzumab-resistant HER2-positive breast cancer cells, could indeed inhibit the cellular luciferase activity in a reporter construct containing the 3′-UTR of IGF1R. Overexpression of miR-375 restored the sensitivity of cells to trastuzumab, while inhibition of miR-375 conferred trastuzumab resistance on HER2-positive breast cancer cells. Blockade of DNA methylation and histone deacetylation restored the expression of miR-375 in trastuzumab-resistant cells. A reverse correlation between the levels of miR-375 and IGF1R was validated in clinical breast cancers. Conclusions Epigenetic silencing of miR-375 causes the upregulation of IGF1R, which at least partially underlies trastuzumab resistance of breast cancer cells. Our study has implications for miR-375 as a potential target in combination with trastuzumab for treating HER2-positive breast cancers.
Databáze: OpenAIRE
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