GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling

• 成果类型: Article
• 署名作者: Karner, Emmet R.; Wang, Mengdie; Goel, Hira Lal; Mercurio, Arthur M.
• 署名单位: University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8923
• 发表日期: 2025-08-26
• 关键词: mammary-gland development; single-cell; breast; differentiation; identification; sensitivity; metastasis; suppresses; generation; resource

摘要

a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are composed of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single- cell RNA- sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin (31 and its downstream signaling cascade. This observation led us to demonstrate that integrin (31 signaling is necessary for 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 is essential for ferroptosis. The repression of integrin (31 by GATA3 inhibits this signaling pathway, rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.