Abstract P5-03-09: Eribulin affects E-cadherin localization consistent with a reversal of the epithelial-to-mesenchymal transition
Authors: Dybdal-Hargreaves NF , Rohena CC , Risinger AL , Mooberry SL 
Published: May 2016

Microtubule targeting agents (MTAs) are some of the most important compounds used to treat breast cancer. While both microtubule stabilizers and destabilizers have utility against breast cancers, not all patients respond and there are differences among the agents. Eribulin is a microtubule depolymerizer used to treat patients with locally advanced or metastatic breast cancerwho have previously received at least two chemotherapeutic regimens, including an anthracycline and a taxane. Our goal was to compare the effects of eribulin to four other clinically relevant MTAs on signaling processes important for cancer cell metastasis that are known to be regulated by the cytoskeleton. One process is the appropriate localization of E-cadherin, which plays a critical role in maintaining an epithelial phenotype by facilitating the ability of cells to form cell-cell contacts. These contacts help prevent cell motility and epithelial to mesenchymal transition (EMT) by sequestering several proteins involved in EMT at the plasma membrane, including β-catenin. E-cadherin is absent from the cell membrane in cells with a mesenchymal phenotype. We hypothesized that eribulin could affect the internalization of E-cadherin and promote its retention at the cell periphery and that it might do so differently than other MTAs because eribulin has been shown to reverse EMT in breast cancer cells and in xenograft models. Mesenchymal breast cancer HCC1937 cells were treated for 2 hr with MTAs using a concentration that caused a similar degree of microtubule disruption and localization of E-cadherin was evaluated. The microtubule destabilizers eribulin and vinorelbine promoted a localization of E-cadherin to the plasma membrane. In contrast, the microtubule stabilizers paclitaxel, docetaxel and ixabepilone caused E-cadherin to localize to internal structures. β-catenin, a protein bound by E-cadherin, also became enriched at the cell periphery after microtubule destabilizer treatment. In the more epithelial MCF-7 cell line, E-cadherin was constitutively localized at the cell periphery and the MTAs had no effect on this localization, consistent with the epithelial phenotype. Src family kinases (SFKs) are known to promote the internalization and degradation of E-cadherin and to promote EMT. Accordingly, the SFK inhibitor dasatinib caused effects similar to eribulin and vinorelbine by promoting the localization of E-cadherin to the plasma membrane in the mesenchymal HCC1937 cell line. Subsequent studies supported this result and demonstrated the increased activity of the combination of eribulin and dasatinib in HCC1937 cells. The ability of eribulin to rapidly induce changes in E-cadherin localization is consistent with its ability to reverse EMT. Studies are ongoing to evaluate whether eribulin's effects are mediated through the ability of SFKs to regulate E-cadherin. Our results show differences between microtubule stabilizers and destabilizers and are consistent with the previously shown ability of eribulin to reverse EMT.

Funding for this work provided by Eisai Inc.

Citation Format: Dybdal-Hargreaves NF, Rohena CC, Risinger AL, Mooberry SL. Eribulin affects E-cadherin localization consistent with a reversal of the epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-09.