PDF(Pubmed)
Abstract：
UNASSIGNED: Studies highlighted the bidirectional crosstalk between the HER family members in breast cancer as resistance mechanism to anti-HER agents. Cross-signaling between HER2/EGFR and ER/IGF1R could play role in the development of resistance to therapeutics hence stimulating cell growth. To overcome this resistance, combined therapies targeting both pathways simultaneously have been proposed as an effective strategy. The involvement of miRNAs in resistance of targeted therapies like trastuzumab was demonstrated in recent studies. Hence the regulation of miRNAs in resistance state could reverse the cell behaviour to drugs. Previously we found that overexpression of miR-770-5p downregulated AKT and ERK expression through HER2 signaling and potentiated the effect of trastuzumab. In this study we examined the impact of miR-770-5p on trastuzumab resistance.
UNASSIGNED: Cells were treated with tamoxifen or trastuzumab to examine their role in bidirectional crosstalk. The molecule mechanism of miR-770-5p on HER2/EGFR/IGF1R bidirectional crosstalk was explored by western blot. The expression of miR-770-5p in trastuzumab resistant cells was examined by q-PCR. To investigate the effect of miR-770-5p on cancer cell proliferation in trastuzumab resistance state, resistant cells were analyzed by iCELLigence real-time cell analyzer.
UNASSIGNED: miR-770-5p expression was significantly downregulated in trastuzumab-resistant BT-474 and SK-BR-3 cells. Overexpression of miR-770-5p sensitized the resistant cells to trastuzumab, as evidenced by reduced cell proliferation and increased cell viability. Additionally, in resistant cells, increased expression and activation of EGFR and IGF1R were observed. However, miR-770-5p overexpression resulted in decreased phosphorylation of AKT and ERK, indicating its suppressive role in EGFR/HER2 signaling. Furthermore, miR-770-5p downregulated the expression of IGF1R and mTOR, suggesting its involvement in regulating the escape signaling mediated by IGF1R in resistance.
UNASSIGNED: In conclusion, our findings demonstrate the critical role of miR-770-5p in regulating bidirectional crosstalk and overcoming trastuzumab resistance in breast cancer cells. These results highlight the potential of miR-770-5p as a therapeutic target to improve the efficacy of targeted therapies and address resistance mechanisms in breast cancer.
UNASSIGNED: Cells were treated with tamoxifen or trastuzumab to examine their role in bidirectional crosstalk. The molecule mechanism of miR-770-5p on HER2/EGFR/IGF1R bidirectional crosstalk was explored by western blot. The expression of miR-770-5p in trastuzumab resistant cells was examined by q-PCR. To investigate the effect of miR-770-5p on cancer cell proliferation in trastuzumab resistance state, resistant cells were analyzed by iCELLigence real-time cell analyzer.
UNASSIGNED: miR-770-5p expression was significantly downregulated in trastuzumab-resistant BT-474 and SK-BR-3 cells. Overexpression of miR-770-5p sensitized the resistant cells to trastuzumab, as evidenced by reduced cell proliferation and increased cell viability. Additionally, in resistant cells, increased expression and activation of EGFR and IGF1R were observed. However, miR-770-5p overexpression resulted in decreased phosphorylation of AKT and ERK, indicating its suppressive role in EGFR/HER2 signaling. Furthermore, miR-770-5p downregulated the expression of IGF1R and mTOR, suggesting its involvement in regulating the escape signaling mediated by IGF1R in resistance.
UNASSIGNED: In conclusion, our findings demonstrate the critical role of miR-770-5p in regulating bidirectional crosstalk and overcoming trastuzumab resistance in breast cancer cells. These results highlight the potential of miR-770-5p as a therapeutic target to improve the efficacy of targeted therapies and address resistance mechanisms in breast cancer.
摘要：
■研究强调了乳腺癌中HER家族成员之间的双向串扰作为抗HER药物的耐药机制。HER2/EGFR和ER/IGF1R之间的交叉信号传导可能在对治疗剂的抗性发展中起作用,因此刺激细胞生长。为了克服这种阻力，同时靶向两种途径的联合治疗被认为是一种有效的策略.在最近的研究中证明了miRNA参与靶向治疗如曲妥珠单抗的抗性。因此，miRNA在耐药状态下的调节可以逆转细胞对药物的行为。以前我们发现miR-770-5p的过表达通过HER2信号传导下调AKT和ERK表达，并增强曲妥珠单抗的作用。在这项研究中，我们检查了miR-770-5p对曲妥珠单抗耐药性的影响。
■用他莫昔芬或曲妥珠单抗处理细胞以检查它们在双向串扰中的作用。通过westernblot探讨miR-770-5p对HER2/EGFR/IGF1R双向串扰的分子机制。通过q-PCR检测miR-770-5p在曲妥珠单抗抗性细胞中的表达。探讨miR-770-5p对曲妥珠单抗耐药状态下癌细胞增殖的影响,用iCELLigence实时细胞分析仪分析耐药细胞。
■miR-770-5p表达在曲妥珠单抗抗性BT-474和SK-BR-3细胞中显著下调。miR-770-5p的过表达使耐药细胞对曲妥珠单抗敏感，如减少的细胞增殖和增加的细胞活力所证明的。此外,在抗性细胞中，观察到EGFR和IGF1R的表达和激活增加。然而,miR-770-5p过表达导致AKT和ERK磷酸化降低,表明其在EGFR/HER2信号传导中的抑制作用。此外，miR-770-5p下调IGF1R和mTOR的表达,提示其参与调节抗性中IGF1R介导的逃逸信号。
■总而言之，我们的研究结果表明,miR-770-5p在调节乳腺癌细胞双向串扰和克服曲妥珠单抗耐药方面的关键作用.这些结果突出了miR-770-5p作为治疗靶标以提高靶向疗法的功效和解决乳腺癌耐药机制的潜力。
■用他莫昔芬或曲妥珠单抗处理细胞以检查它们在双向串扰中的作用。通过westernblot探讨miR-770-5p对HER2/EGFR/IGF1R双向串扰的分子机制。通过q-PCR检测miR-770-5p在曲妥珠单抗抗性细胞中的表达。探讨miR-770-5p对曲妥珠单抗耐药状态下癌细胞增殖的影响,用iCELLigence实时细胞分析仪分析耐药细胞。
■miR-770-5p表达在曲妥珠单抗抗性BT-474和SK-BR-3细胞中显著下调。miR-770-5p的过表达使耐药细胞对曲妥珠单抗敏感，如减少的细胞增殖和增加的细胞活力所证明的。此外,在抗性细胞中，观察到EGFR和IGF1R的表达和激活增加。然而,miR-770-5p过表达导致AKT和ERK磷酸化降低,表明其在EGFR/HER2信号传导中的抑制作用。此外，miR-770-5p下调IGF1R和mTOR的表达,提示其参与调节抗性中IGF1R介导的逃逸信号。
■总而言之，我们的研究结果表明,miR-770-5p在调节乳腺癌细胞双向串扰和克服曲妥珠单抗耐药方面的关键作用.这些结果突出了miR-770-5p作为治疗靶标以提高靶向疗法的功效和解决乳腺癌耐药机制的潜力。
