Abstract 6097: Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4

Abstract Ferroptosis is an iron dependent form of regulatory cell death caused by the accumulation of lipid peroxides that can be exploited as a therapeutic for carcinomas and possibly other cancers. However, some populations of carcinoma cells resist ferroptosis, especially those with an epithelial phenotype but the mechanisms that promote resistance are poorly understood. We discovered that ferroptosis resistance in triple-negative breast cancer cells (TNBC) with an epithelial phenotype is dependent on expression of the integrin β4 and its ligand laminin 332 (LM332). LM332 and the integrin β4 maintain an epithelial cell state by downregulation of the EMT factor ZEB1. We further demonstrate that repression of ZEB1 by integrin β4 and LM332 promotes YAP/TAZ-mediated transcription of the C2 subunit of LM332, activating a positive feedback loop. Lastly, we observed that disrupting the β4/LM332 signaling axis sensitizes epithelial TNBC cells to ferroptosis by inducing ZEB1 expression. Our findings reveal a novel role for the extracellular matrix in promoting ferroptosis resistance by sustaining an epithelial phenotype and they suggest potential therapeutic strategies for overcoming this resistance. Citation Format: Emmet R. Karner, Hira Lal Goel, Arthur M. Mercurio. Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6097.