Abstract 657: Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells

Abstract

Abstract Breast cancer is the second most diagnosed cancer in women and it is estimated that approximately 40,000 women die every year from this disease in this country alone. The overexpression of EGFR in breast cancer is associated with drug resistance and an aggressive nature resulting in an overall poor outcome. The EGFR signaling pathway requires internalization of the receptor, endosomal translocation and in some cases nuclear accumulation of the receptor. These processes are dependent on functional microtubules. Microtubule targeting agents (MTAs) have been used with great success in the treatment of breast cancer alone and in combination with other agents. MTAs impair microtubule dynamics, which results in the inhibition of mitosis. Microtubules are additionally important in cellular signaling events including cellular transport of the EGFR. The effects of the microtubule stabilizer taccalonolide AJ on EGFR transport and activation in breast cancer cells were compared to the effects of paclitaxel. Our results show that microtubule stabilization interrupts the cellular trafficking of EGFR, leading to the retention of the receptor in the cell periphery.. Taccalonolide AJ and paclitaxel impaired the association of EGFR with the early endosome and delayed its association with the lysosome. This disruption in cellular transport also led to decreased phosphorylation of EGFR downstream targets AKT, ERK1/2 and STAT3, with taccalonolide AJ being the more effective inhibitor. Our studies show that microtubule stabilizers also prevent the association of EGFR with the Golgi instead leading to the fragmentation of this organelle. Paclitaxel caused a higher degree of Golgi fragmentation and it was observed in nearly all cells. The inhibition of EGFR localization to the Golgi caused by taccalonolide AJ and paclitaxel suggests that microtubule stabilization interferes with the trafficking of EGFR to the nucleus. This was confirmed by our results showing that microtubule stabilization impairs the nuclear transport of EGFR in breast cancer cells. Not surprisingly, in this case, paclitaxel was much more effective at preventing this nuclear accumulation. These studies highlight the utility and versatility of microtubule stabilizers and suggest the potential for combination treatments with microtubule stabilizers and small molecule inhibitors of EGFR and EGFR dependent pathways in breast cancer. Citation Format: Cristina Coral Rohena, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry. Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 657. doi:10.1158/1538-7445.AM2015-657