Abstract P2-02-07: Targeting iron metabolism in breast cancer: Ferroptosis and genome stability

Iron-sulfur clusters are cell-essential protein cofactors in at least 48 human enzymes supporting diverse cellular functions, including genomic integrity and oxidative phosphorylation, and acting as molecular sensors for oxygen and iron levels. We recently described that breast cancer cells are particularly dependent upon robust iron-sulfur cluster biosynthesis for the survival of elevated oxygen conditions, including seeding lung metastases (1). Moreover, we found that even partially blocking cluster synthesis activated an iron-starvation response, rendering breast cancer cells susceptible to oxidative stress and death by ferroptosis (1). However, the precise mechanisms underlying these phenotypes remain to be fully elucidated. Here, we find that basal-like breast cancer cells are particularly susceptible to suppression of iron-sulfur cluster biosynthesis. By systematically evaluating proteins containing iron-sulfur clusters, we discovered that this susceptibility lies in the intrinsic vulnerability of basal-like breast cancer cells to genomic instability. These results have enabled us to define specific molecular targets in basal-like breast cancer which induce DNA damage, replication fork instability, and apoptosis, with striking subtype specificity. Our findings have broad implications for the underlying differences in genomic integrity in basal-like and luminal breast cancer subsets, and will inform future novel strategies to target genomic integrity in basal-like breast cancer. 1. Alvarez S, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, and Possemato R. NFS1 Undergoes Positive Selection in Lung Tumors and Protects Cells From Elevated Oxygen Levels and Ferroptosis, Nature. 2017 Nov 30;551(7682):639-643. This work was supported by a Susan G. Komen Career Catalyst Award and the NCI (R01 CA214948). Citation Format: Possemato RL, Sviderskiy VO, Alvarez SW, Terzi EM. Targeting iron metabolism in breast cancer: Ferroptosis and genome stability [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 P2-02-07.