Targeting of HER3 with Functional Cooperative miRNAs Enhances Therapeutic Activity in HER2-Overexpressing Breast Cancer Cells

Abstract

BackgroundThe HER3 receptor functions as a major cause of drug resistance in cancer treatment. It is believed that therapeutic targeting of HER3 is required to improve patient outcomes. It is not clear whether a novel strategy with two functional cooperative miRNAs would effectively inhibit erbB3 expression and potentiate the anti-proliferative/anti-survival effects of a HER2-targeted therapy (trastuzumab) and chemotherapy (paclitaxel) on HER2-overexpressing breast cancer cells.ResultsCombination of miR-125a and miR-205, as compared to either miRNA alone, potently inhibited expression of HER3 in HER2-overexpressing breast cancer BT474 cells. Co-expression of the two miRNAs not only reduced the levels of phosphorylated erbB3 (P-erbB3), Akt (P-Akt), and Src (P-Src), it also inhibited cell proliferation and increased cells at G1 phase. A multi-miRNA lentiviral vector - the cluster of miR-125a and miR-205 - was constructed to simultaneously express the two miRNAs in HER2-overexpressing breast cancer cells. Concurrent expression of miR-125a and miR-205 via the miRNA cluster transfection significantly enhanced trastuzumab-mediated growth inhibition and cell cycle G1 arrest in BT474 cells and markedly increased paclitaxel-induced apoptosis in another HER2-overexpressing breast cancer cell line HCC1954.ConclusionsHere, we showed that functional cooperative miRNAs effectively suppressed erbB3 expression. This novel approach targeting of HER3 was able to enhance the therapeutic efficacy of trastuzumab and paclitaxel against HER2-overexpressing breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12575-018-0081-x) contains supplementary material, which is available to authorized users.

Development of Effective Therapeutics Targeting HER3 for Cancer Treatment

“…Moreover, our study further support the idea that functional cooperation exists among the multiple binding sites of one miRNA, which is in agreement with our recent report showing that the miR-125a/miR-205 cluster potently inhibits HER3 expression in HER2-over-expressing breast cancer cells [24]. It is likely that the multiple binding sites of one miRNA and the “sister” miRNAs, which have common targets [26], act synergistically to repress the target, suggesting that the miRNAs with multiple binding sites may be more promising in miRNA-replacement therapy.…”

“…Due to the lack of, or weak, kinase activity [ 9 , 10 ], targeting HER3 with a blocking antibody (Ab) is the only strategy currently being examined in pre-clinical studies and clinical evaluation in cancer patients [ 17 – 21 ]. Recent studies offer new hopes to develop epigenetic approaches, such as using a histone deacetylase inhibitor (HDACi) [ 22 , 23 ] specific miRNAs [ 24 – 26 ], or by targeting HER3 and its key downstream mediators.…”

Long non-coding RNA SNHG5 promotes glioma progression via miR-205/E2F3 axis

“…MiR-205 functions as a tumour suppressor in human cancers, such as breast cancer, prostatic carcinoma and oral squamous cell carcinoma [27][28][29]. Our study found that miR-205 suppressed the glucose uptake, migration and invasion of glioma cells.…”

miR-205: A Potential Biomedicine for Cancer Therapy

“…This combination showed a drastic increase in G1 phase cell cycle arrest (77.52%) and it also modulated the expression of cell cycle related proteins such as E2F1 (decreased), p27 and Cyclin D1 (both increased) after trastuzumab treatment. Moreover, this cluster of miR-125a and miR-205 enhanced the anti-cancer properties of paclitaxel by further promoting the apoptosis as confirmed through ELISA-apoptosis assay, and cleaved PARP and Caspases 3/8 [ 207 ].…”