Abstract 477: Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells

Abstract

Abstract Introduction: ErbB3 serves as a critical co-receptor of erbB2 and plays a vital role in the development of erbB2-overexpressing (erbB2+) breast cancer. It is thought to be an important compensatory target for combinatorial strategy to improve the treatments for erbB2+ breast cancer patients. MiRNAs regulate gene expression by the sequence-specific targeting of mRNAs, leading to translational repression or mRNA degradation. ErbB3 is a direct target of both miR-125a and miR-205. Here, we study the potential activity of miRNA based erbB3-targeted therapy in erbB2+ breast cancer cells. Methods: Cell growth assays were used to determine cell viability. Western blot analyses were performed to assess the expression and activation of proteins. Flow cytometry analysis was carried out to examine cell cycle progression. Lentiviral vector containing one or two miRNAs was used to ectopically express miR-125a and/or miR-205. Results: Co-expression of miR-125a and miR-205 showed a potent activity to downregulate erbB3 while single miRNA had no or little effect on erbB3 when miR-125a or miR-205 was only increased below 10-fold in BT474 cells. Combination of the two miRNAs not only resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and the downstream signaling kinases Akt (P-Akt) and Src (P-Scr), it also inhibited cell proliferation and increased the cells at G1 phase. More importantly, concomitant expression of the two miRNAs significantly enhanced trastuzumab-mediated growth inhibition and cell cycle G1 arrest in BT474 cells. Interestingly, the expression levels of miR-125a, but not miR-205 in the trastuzumab-resistant BT474-HR20 cells were much lower than that in the parental BT474 cells. Ectopic expression of miR-125a alone profoundly inhibited proliferation of BT474-HR20 cells. These data suggested that reduced miR-125a might be a novel mechanism leading to trastuzumab resistance; and upregulation of miR-125a could be a useful tool to abrogate the resistance. Conclusions: Co-expression of miR-125a and miR-205 is a new approach to inhibit erbB3. Specific targeting of erbB3 via the functional cooperative miRNAs enhances efficacy of trastuzumab against erbB2+ breast cancer cells. Our data support further exploration of the possible role of miR-125a in the development of trastuzumab resistance. Keywords: ErbB3, ErbB2, miRNA, Trastuzumab, Breast Cancer Citation Format: Hui Lyu, Jingcao Huang, Bolun Wang, Amy Han, Bolin Liu. Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 477.