Gene Expression Profiling Reveals Epithelial Mesenchymal Transition (EMT) Genes Can Selectively Differentiate Eribulin Sensitive Breast Cancer Cells

Abstract

ObjectivesEribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro.ResultsWe determined the sets of genes that were differentially altered between eribulin and paclitaxel treatment in breast, endometrial, and ovarian cancer cell line panels. Our unsupervised clustering analyses revealed that expression profiles of gene sets altered with treatments were correlated with the in vitro antiproliferative activities of the drugs. Several tubulin isotypes had significantly lower expression in cell lines treated with eribulin compared to paclitaxel. Pathway enrichment analyses of gene sets revealed that the common pathways altered between treatments in the 3 cancer panels were related to cytoskeleton remodeling and cell cycle regulation. The epithelial-mesenchymal transition (EMT) pathway was enriched in genes with significantly altered expression between the two drugs for breast and endometrial cancers, but not for ovarian cancer. Expression of genes from the EMT pathway correlated with eribulin sensitivity in breast cancer and with paclitaxel sensitivity in endometrial cancer. Alteration of expression profiles of EMT genes between sensitive and resistant cell lines allowed us to predict drug sensitivity for breast and endometrial cancers.ConclusionGene expression analysis showed that gene sets that were altered between eribulin and paclitaxel correlated with drug in vitro antiproliferative activities in breast and endometrial cancer cell line panels. Among the panels, breast cancer provided the strongest differentiation between eribulin and paclitaxel sensitivities based on gene expression. In addition, EMT genes were predictive of eribulin sensitivity in the breast and endometrial cancer panels.

High‐level expression of ARID1A predicts a favourable outcome in triple‐negative breast cancer patients receiving paclitaxel‐based chemotherapy

“…Genetic mutation of the chromatin remodelling complex has been identified as a mechanism of tumour occurrence and development . Here, we analyse the transcriptional profiling of paclitaxel‐sensitive DU4475 and paclitaxel‐resistant MDA‐MB436 without or with paclitaxel treatment, which was determined previously . We found that the AT‐rich interaction domain 1A (ARID1A) is up‐regulated in DU4475 cells but is down‐regulated in MDA‐MB436 cells.…”

Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition

“…EMT is a process in which epithelial cells acquire mesenchymal properties and show loss of intercellular cohesion, increased cellular migration, and increased resistance to anticancer agents. Importantly, the EMT signature correlates with eribulin resistance in breast cancer cells in vitro (29), cisplatin resistance in ovarian cancer (30,31), and resistance to gemcitabine, 5-FU and cisplatin in pancreatic cancer (32). Our previous study demonstrated that the EMT-associated genes N-cadherin , vimentin and Snail were upregulated in HOC313 cells (14).…”

Eribulin Does Not Prevent Epithelial-to-Mesenchymal Transition in HT-29 Intestinal Epithelial Cells

“…A reason for this result might be that HT-29 IEC already have a distinct epithelial phenotype more similar to a physiologically configured epithelium, while TNBC seems to have a more stem-cell like mesenchymal behavior corresponding to the cells of an aggressively metastatic type of cancer. It has already been shown that the expression of some EMT marker genes predicts Eribulin sensitivity in some cell lines [24]. Interestingly, Eribulin not only enhanced the mRNA expression of the EMT markers SLUG and vimentin but also promoted E-cadherin expression, a marker associated with an epithelial phenotype.…”

“…After 12 h, the medium was replaced by low-glucose DMEM without additives. After 8 h, the medium was replaced by low-glucose DMEM with 0.1, 0.5, 1, 5, 50, 100, or 500 ng/mL Eribulin as indicated and stimulated for 4,8,24,48, and 72 h. Cell supernatant was used to perform an LDH assay (Sigma-Aldrich, St. Louis, Missouri, USA), which quantifies LDH released after cell damage. Cell Counting Kit-8 (CCK8; Dojindo Molecular Technologies, Rockville, Maryland, USA) was used to evaluate cell proliferation and cytotoxicity.…”