Single-Cell Image-Based Analysis Reveals Chromatin Changes during the Acquisition of Tamoxifen Drug Resistance

Abstract

Cancer drug resistance is the leading cause of cancer related deaths. The development of drug resistance can be partially contributed to tumor heterogeneity and epigenetic plasticity. However, the detailed molecular mechanism underlying epigenetic modulated drug resistance remains elusive. In this work, we systematically analyzed epigenetic changes in tamoxifen (Tam) responsive and resistant breast cancer cell line MCF7, and adopted a data-driven approach to identify key epigenetic features distinguishing between these two cell types. Significantly, we revealed that DNA methylation and H3K9me3 marks that constitute the heterochromatin are distinctively different between Tam-resistant and -responsive cells. We then performed time-lapse imaging of 5mC and H3K9me3 features using engineered probes. After Tam treatment, we observed a slow transition of MCF7 cells from a drug-responsive to -resistant population based on DNA methylation features. A similar trend was not observed using H3K9me3 probes. Collectively, our results suggest that DNA methylation changes partake in the establishment of Tam-resistant breast cancer cell lines. Instead of global changes in the DNA methylation level, the distribution of DNA methylation features inside the nucleus can be one of the drivers that facilitates the establishment of a drug resistant phenotype in MCF7.

Developmental Pb exposure increases AD risk via altered intracellular Ca2+ homeostasis in hiPSC-derived cortical neurons

“…We then assessed nuclear morphology and chromatin compactness. Nuclear area and roundness were measured using DAPI-stained nuclei from Day 25 and Day 45 following our established protocol ( 39 , 51 , 52 , 53 ). The data were summarized in Fig.…”

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

“…Plasticity in chemotherapy resistance is reflected in non-small cell lung cancer (NSCLC) by epigenetic alterations that allow tumor cells to adapt to new microenvironments after drug administration ( 47 ). Tamoxifen treatment causes acquired drug resistance in MCF7 breast cancer cells by altering the DNA methylation status ( 48 ). It has been demonstrated that epigenetic silencing of Spalt-like transcription factor 2 (SALL2) contributes to tamoxifen resistance in breast cancer by activating the AKT/mTOR pathway ( 49 ).…”