Abstract P5-04-04: Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines

Abstract

Abstract Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While these drugs were classically identified as only antimitotic agents, recent evidence demonstrates that the ability of MTAs to disrupt key signaling components in interphase cells likely contributes to their anticancer actions. Yoshida and colleagues demonstrated that eribulin reverses TGF-β-induced epithelial-to-mesenchymal transition (EMT) in preclinical models of triple negative breast cancer (TNBC) within 7days. To gain a deeper understanding of the interphase effects of eribulin in comparison with other MTAs on the TGF-β signaling pathway, we tested the hypothesis that a short-term, 2 h treatment of TNBC cells with MTAs would disrupt TGF- β signaling. The effects of the microtubule destabilizers eribulin and vinorelbine and the microtubule stabilizers paclitaxel and ixabepilone on downstream targets of the TGF-β pathway were evaluated in two TNBC cell lines. In the mesenchymal type BT-549 cells, eribulin and vinorelbine significantly inhibited TGF-β induced expression of Snail and Slug, while the microtubule stabilizers had no effect on their expression. In the basal-like 1 type HCC1937 cells, the microtubule destabilizers inhibited the expression of Snail when compared to vehicle and stabilizer-treated cells, but caused increased expression of Slug. These data suggest that MTAs have different effects on the TGF-β signaling pathway in distinct molecular contexts. Our efforts are directed towards deciphering the effects of eribulin and other MTAs on the TGF- β pathway and how this contributes to differential sensitivity. Preliminary data suggest that eribulin initiated inhibition of Snail and Slug in BT-549 cells is mediated by the scaffold protein NEDD9 and we are testing whether the differential levels of expression of NEDD9 help explain the differences in the effects of eribulin in BT-549 and HCC1937 cells. These results will begin to decipher differences among MTAs in different molecular contexts and might help identify biomarkers for optimal therapies. Funding for this work was provided by Eisai Inc. Citation Format: Kaul R, Risinger AL, Mooberry SL. Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-04-04.