Abstract P5-03-08: Eribulin impairs the transport of TGF-{beta} type I receptor leading to inhibition of downstream non-canonical TGF-{beta} signaling necessary for cancer metastasis and survival

Microtubule targeting agents (MTAs) continue to be some of the most valuable drugs used in the treatment of breast cancers. While decades of research have shown that these drugs cause mitotic arrest in cells by suppressing the dynamic instability of microtubules, recent evidence demonstrates that the ability of MTAs to disrupt microtubule-dependent transport of key signaling components, including proteins and microRNAs, in interphase cells likely contributes to their anticancer actions. TGF-β receptors are known to undergo constant cycling from the plasma membrane to intracellular portions of the cell, a process which is microtubule dependent. This microtubule-dependent trafficking has been shown to regulate the nuclear translocation of the TGF-β type I receptor, TGFβR1. Nuclear translocation of TGFβR1 activates the expression of genes including Snail and MMP2, which facilitate the invasiveness, motility and metastasis of cancer cells. We tested the hypothesis that a 2 h treatment of breast cancer cells with eribulin or 4 other clinically relevant MTAs, would differentially disrupt interphase microtubules and alter the internalization and trafficking of TGFβR1 to the nucleus; thereby impacting downstream signaling events. Cells were serum starved for 12 hours and then treated for 2 h with concentrations of MTAs that caused comparable disruption of the interphase microtubule network; 100 nM was used for the destabilizers, eribulin and vinorelbine and 1 μM was used for th...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Poster Session Abstracts Source Type: research