Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R.
Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R.
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miR-375的表观遗传沉默通过靶向IGF1R诱导HER2阳性乳腺癌的曲妥珠单抗耐药
DOI：
10.1186/1471-2407-14-134
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发表时间：
2014-02-26
期刊：
影响因子：
3.8
通讯作者：
Jia LT
中科院分区：
文献类型：
--
作者：
Ye XM;Zhu HY;Bai WD;Wang T;Wang L;Chen Y;Yang AG;Jia LT
背景人源化erbB 2/HER 2单克隆抗体曲妥珠单抗（Herceptin）的耐药已成为HER 2阳性乳腺癌靶向治疗的关键障碍。替代生长因子受体，特别是胰岛素样生长因子1受体（IGF 1 R）的激活，代表了一个共同的特点，曲妥珠单抗难治性细胞，然而，潜在的机制仍然hierarchic. MethodsTrastuzumab耐药乳腺癌SKBr-3细胞产生的长期在体外培养的SKBr-3细胞中存在的曲妥珠单抗。在通过微阵列分析筛选的差异表达的微小RNA（miRNA）中，研究了预测靶向IGF 1 R的候选miRNA在赋予曲妥珠单抗抗性中的作用。结果miR-375在曲妥珠单抗耐药的HER 2阳性乳腺癌细胞中表达下调，并被预测为靶向IGF 1 R，在含有IGF 1 R 3′-UTR的报告基因构建体中，miR-375确实可以抑制细胞荧光素酶活性。miR-375的过表达恢复了细胞对曲妥珠单抗的敏感性，而miR-375的抑制赋予了HER 2阳性乳腺癌细胞对曲妥珠单抗的抗性。阻断DNA甲基化和组蛋白去乙酰化可恢复曲妥珠单抗耐药细胞中miR-375的表达。miR-375和IGF 1 R的水平之间的反向相关性在临床breast cancers.Conclusionsepigenetic沉默的miR-375的原因上调IGF 1 R，这至少部分地基于曲妥珠单抗耐药的乳腺癌细胞。我们的研究表明，miR-375是与曲妥珠单抗联合治疗HER 2阳性乳腺癌的潜在靶点。
BackgroundResistance 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.MethodsTrastuzumab-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.ResultsmiR-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.ConclusionsEpigenetic 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.
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