Abstract P5-03-08: Eribulin-induced EpCAM expression provides drug resistance in triple-negative breast cancer cells

Abstract

Abstract Breast cancer is the most common cancer in women in the world. Among breast cancer subtypes, triple-negative breast cancer is aggressive. Because there is no effective therapy for triple-negative breast cancer, development of a novel therapeutic strategy is required. Eribulin, a derivative of halicondrin B, is an anticancer chemical. Eribulin treatment has been approved in many countries for patients with metastatic or inoperable breast cancer, including triple-negative breast cancer. The known functions of Eribulin are inhibition of microtubule polymerization and induction of the expression of epithelial genes in breast cancer cells. However, the function of Eribulin-induced genes on the therapy for patients with triple-negative breast cancer remains unclear. EpCAM (Epithelial cell adhesion molecule) is one of epithelial markers and known as a cell-cell adhesion molecule. In addition, EpCAM expression is involved in drug resistance in cancer. We therefore focused on EpCAM expression in Eribulin-treated breast cancer cells. We used MDA-MB-231 cells that is a commonly used triple-negative breast cancer cell line. We treated cells with 10 nM Eribulin and observed inhibition of cell growth. In the same condition, we found up-regulation of EpCAM expression in both mRNA and protein levels. In mouse xenograft model with MDA-MB-231 cells, EpCAM expression was detected in whole tumor at 96 h after Eribulin administration. We analyzed the effect of other microtubule polymerization inhibitors, nocodazole and colchicine, on EpCAM induction. In the results, there was no up-regulation of EpCAM expression in cells treated with these chemicals, suggesting that EpCAM expression is not induced by inhibition of microtubule polymerization and growth inhibition. To analyze EpCAM function on Eribulin treatment, we constructed shRNA-mediated EpCAM knockdown system. We introduced EpCAM knockdown in MDA-MB-231 cells and treated with Eribulin. In the results of cell growth assays, the cell number of Eribulin-treated EpCAM-knockdown cells was significantly smaller than that of Eribulin-treated control-shRNA cells, whereas no change was observed between solvent-treated control-shRNA and EpCAM-knockdown groups. In mouse xenograft experiments, EpCAM-knockdown cells showed smaller tumor weights than control-shRNA cells after administration of Eribulin. These results indicate that EpCAM expression provides Eribulin resistance in breast cancer cells. In conclusion, we found Eribulin-induced EpCAM expression in triple-negative breast cancer cells. The EpCAM expression provides Eribulin resistance both in vitro and in vivo. These suggest that a combination of Eribulin treatment and EpCAM inhibition may improve therapy for breast cancer. Citation Format: Tanaka S, Itou J, Sato F, Toi M. Eribulin-induced EpCAM expression provides drug resistance in triple-negative breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-08.