Abstract P4-07-06: MicroRNAs associated with acquired taxane resistance in a breast cancer cell line model

Abstract

Abstract Background: Acquired chemoresistance remains the major cause of therapeutic failure in the treatment of breast cancer. Improved knowledge of the transition from drug sensitive to resistant breast cancer will pave the way for novel preventative and therapeutic strategies. MicroRNAs (miRNA) are endogenous, small non-coding RNAs that regulate gene expression by targeting the 3'UTR region of messenger RNAs. There is a growing body of evidence to suggest miRNAs may be involved in the development of chemoresistance and may play a role in the regulation of drug resistance pathways. Methods: An in vitro model of paclitaxel resistance was developed through the generation of resistant MDA-MB-231 cell lines by serial culture in escalating doses of taxane until resistance was achieved. The chemoresistant model was used to compare differential miRNA expression with the sensitive, parental line using the Nanostring® platform, analysing 800 human miRNAs. Confirmation of differential expression was performed by QRT-PCR. Results: This analysis resulted in 30 significantly altered miRNA (1.5 fold, p value < 0.05) at 25nM paclitaxel and 48 significantly altered miRNA at 50nM paclitaxel. The top up-regulated miRNA cluster in MDA-MB-231 25PACR is hsa-miR-548l (fold change: 2.89, p value: 0.016) and top down-regulated was hsa-miR-449a (fold change: -4.1. p value: 0.001). In MDA-MB-231 50PACR the top up-regulated miRNA cluster is hsa-miR-193a-5p (fold change: 3.746, p value: 0.008) and the top down-regulated miRNA cluster is hsa-miR-135a (fold change: -4.085, p value: 0.001). To explore the molecular mechanisms of the differentially expressed miRNAs in paclitaxel resistance, targets were predicted by in silico analysis. Pathways and networks designated by miRNA targets included the cell cycle, PI3K/Akt pathways and focal adhesion. Conclusion: In this study we identified candidate resistance-associated miRNAs which were differentially expressed between in vitro derived paclitaxel resistant MDA-MB-231 and the sensitive parental line. Further validation to ascertain their role in the transition to a chemoresistant phenotype is currently ongoing. Citation Format: Taylor KJ, Chong T, D'Costa A, Yao C, Gourley C, Cameron DA, Bartlett JMS, Spears M. MicroRNAs associated with acquired taxane resistance in a breast cancer cell line model [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-06.