Mathematical Modeling and Transcriptome Profiling of Breast Cancer Cells During Tamoxifen Treatment Reveal Multiple Trajectories for Resistant Subtypes

Abstract

Cancer cells acquire drug resistance through following non-resistant, pre-resitant and resistant stages. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here, we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing of tamoxifen-treated cells revealed that tamoxifen-resistant cells can be subgrouped into two, one showing cancer stem cell-like metabolic regulation and the other showing high expression of genes encoding adhesion molecules and histone modifying-enzymes. Pseudotime analyses showed a cell transition trajectory to the two resistant subgroups that stems from shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted that inhibition of transition to both subtype would be required to prevent the appearance of tamoxifen resistance.