Abstract P5-08-06: Differential effects of eribulin on key transcription factors snail and slug

Abstract

Abstract Microtubule targeting agents (MTAs) are a mainstay in the treatment of breast cancer and a growing body of evidence demonstrates that they have non-mitotic effects that contribute to their anticancer actions. Even after decades of clinical use, there is much to still be learned about the mechanisms of action these drugs, and differences among them, for optimal utility. MTAs rapidly alter microtubule dynamics, often within minutes, leading to significant changes in oncogenic cellular signaling. We evaluated the early effects of eribulin on key oncogenic signaling pathways following a 2 h incubation using clinically relevant concentrations and compared the effects to those initiated by other MTAs. These studies led to the identification of novel mechanisms by which MTAs disrupt oncogenic signaling and contribute to the reversal of epithelial to mesenchymal transition (EMT), including unanticipated differences among drugs. The TGF-β-mediated expression of the Snail transcription factor is a key driver pathway of EMT in breast cancer. The effects of eribulin and other MTAs on TGF-β-induced, Smad-dependent expression of Snail were evaluated. Our results show that eribulin and vinorelbine, but not paclitaxel or ixabepilone, inhibit the ability of TGF-β to promote the transcriptional induction of Snail by impeding the nuclear transport of Smad2/3 proteins in 4 triple-negative breast cancer cell lines. This study begins to explain how microtubule disruption might contribute to the eribulin-mediated EMT reversal observed in vitro, in vivo, and in patients. Slug is another member of the Snail family of transcription factors that plays a central role in breast cancer EMT. Although Snail and Slug are often grouped together due to functional similarities, it is becoming increasingly clear that Slug has an independent role in regulating stemness and cancer cell survival during partial EMT. In contrast to our findings with Snail, eribulin and vinorelbine, but not paclitaxel or ixabepilone, induced Slug expression independent of TGF-β stimulation in a subset of triple-negative breast cancer cell lines. Studies are ongoing to identify the molecular pathways and consequences of eribulin and vinorelbine-induced Slug induction, which might begin to identify biomarkers of patient response to different MTAs. This work highlights the multifaceted nature of MTA-mediated effects on EMT-associated signaling pathways in breast cancer cells and prompts a reevaluation of their differential efficacy in tumors with distinct molecular profiles. These studies are supported by Eisai Inc. Citation Format: Kaul R, Risinger AL, Mooberry SL. Differential effects of eribulin on key transcription factors snail and slug [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 P5-08-06.