Abstract 1237: Zeb1-mediated autophagy enhances resistance of breast cancer cells to genotoxic drugs

Abstract

Abstract This report presents novel results on the involvement of epithelial to mesenchymal transition (EMT) in the process of autophagy. Autophagy is a highly conserved process of cellular self-digestion that involves the formation of autophagosomes for the delivery of intracellular components and dysfunctional organelles to lysosomes. This process is induced by different signals including starvation, mitochondrial dysfunction, and DNA damage. The molecular link between autophagy and DNA damage is not well understood yet. Importantly, tumor cells utilize the mechanism of autophagy to cope with genotoxic anti-cancer drug therapy. Another mechanism of drug resistance is provided to cancer cells via the execution of the EMT program. One of the critical transcription factors of EMT is Zeb1. Here we demonstrate that Zeb1 is involved in the regulation of autophagy in several breast cancer cell models. On the molecular level, forced expression of Zeb1 in otherwise epithelial cells likely facilitates autophagy through the regulation of several autophagic genes, resulting in increased LC3-II levels, augmented staining with Lysotracker, and increased resistance to genotoxic drugs. On the contrary, the attenuation of Zeb1 expression in TNBC cells led to the opposite effect. Consequently, we propose that Zeb1 augments the resistance of breast cancer cells to genotoxic drugs, at least partially, by promoting autophagy. Collectively, we have uncovered a novel function of Zeb1 in the regulation of autophagy in breast cancer cells. Citation Format: Nick A. Barlev, Olga Fedorova, Alexandra Daks, Eugene M. Tulchinsky. Zeb1-mediated autophagy enhances resistance of breast cancer cells to genotoxic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1237.