Identification of tamoxifen-resistant microRNA expression profiles in breast cancer: En route to precision medicine through establishing new biomarkers

Abstract

BackgroundBreast cancer (BC) is found approximately at 1 million of new cases annually, and mortality reaches 400 thousand. Acquired resistance to tamoxifen limits adjuvant therapy`s potential to combat BC. Notably, up to 50% of ER+ BC cases fail to respond tamoxifen therapy. Elucidating molecular mechanisms of tamoxifen resistance development and transfer is important to develop novel therapies. New biomarkers indicating tamoxifen resistance are also to be found for proper development of precise therapies. Previously we have demonstrated the existence of tamoxifen resistance horizontal transfer at least particularly mediated by exosomes. The latter can carry microRNAs cargo.MethodsIn this work using NGS approaches we investigated the changes of intracellular miRNA content between control cells and cells that acquired resistance to tamoxifen in 3 different ways: a) by prolonged cultivation of cells with tamoxifen (MCF7/T); b) by co-cultivation of MCF7 and MCF7/T (MCF7/R), and c) by cultivation of MCF7 with addition of exosomes derived from MCF7/R (MCF7/exoT).ResultsAll three routes of tamoxifen resistance acquisition in vitro revealed selective changes in a few miRNA levels. There were 8 such miRNA found in MCF7/T cells (with p-value <0.05), 6 miRNAs in MCF7/R, and 5 miRNAs found in MCF7/exoT. Notably, these overlap in 3 miRNAs: miR-30a-5p, miR-484 and miR-1301-3p. Tamoxifen resistance was accompanied by upregulation of miR-30a-5p (∼ 5,2 fold) and downregulation of both miR-484 and miR-1301-3p (∼4,2 and 6,7 fold respectively). Intriguingly miR-30a-5p was also significantly elevated in the exosomes derived from resistant cells indicating this miRNA`s possible involvement into the resistance transfer.ConclusionsTamoxifen resistance acquisition in vitro by MCF7 cells have revealed common patterns of changes in 3 miRNAs levels that can represent special biomarkers connected with tamoxifen resistance of breast cancer cells.Legal entity responsible for the studyThe authors.FundingExperiments were supported by Russian Science Foundation (17-75-10212 – experiments with tamoxifen-resistant cells; 19-15-00245 – experiments with exosomal miRNAs).DisclosureAll authors have declared no conflicts of interest.