ABSTRACT

Understanding mechanisms that determine the response of cells to ferroptotic stress isa timely issue that has significant ramifications for biology and pathology. We inves-tigated these mechanisms in the context of breast cancer where tumors are composedof diverse populations of cancer cells that differ in their ferroptosis sensitivity. Usingsingle- cell RNA-sequencing, we determined that cancer cell populations with luminaldifferentiation are more resistant to ferroptosis than other cells within a heterogeneoustumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3,a transcription factor that promotes luminal differentiation, has a causal role in ferrop-tosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, wefound that GATA3 represses the expression of integrin β1 and its downstream signalingcascade. This observation led us to demonstrate that integrin β1 signaling is necessaryfor sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that isessential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signalingpathway, rendering cells ferroptosis resistant. Together, these data provide insight intomechanisms of ferroptosis sensitivity and resistance that are linked to the cell biologyand signaling pathways of the diverse types of cells present in breast tumors.

E.R. Karner, M. Wang, H.L. Goel, A.M. Mercurio. GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling, Proc Natl Acad Sci U S A. 2025 Aug 19.