Exploit Dimethyl Fumarate to Uncover Druggable Vulnerabilities and Prevent Recurrence of ER plus Breast Cancers
Abstract
Our in vivo tumor studies using two complementary approaches, RNA transcriptomic analysis and chemo proteomics converged on identifying the IRF9/interferon (IFN) axis as critical to tumor recurrence and a therapeutic target of DMF in breast cancer. Next, we focused on two questions: (i) how does IRF9/IFN axis promote tumor recurrence, (ii) the molecular basis ofIRF9 inhibition by DMF. We found that IRF9 expression is higher in luminal tumors compared to other subtypes or normal breast tissue using the TCGA database. IFN signaling is higher in mammospheres (MS), which enrich for cancer stem cells. We found that IRF9 expression is elevated and required for MS formation. DMF treatment inhibits IFN signaling in MS measured by ISGs (interferon stimulated genes) and results in succination of IRF9. We also found that DMF inhibits cytokine stimulated transcription of ISGs. Based on modeling, we hypothesized that succination of IRF9 disrupts its interaction withSTAT2 and was demonstrated using co-IP studies. We conclude that higher IRF9 bestows stem-like properties to promote tumor recurrence. IRF9 can be developed into a new target against tumor recurrence.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2023
- Accession Number
- AD1210496
Entities
People
- Irida Kastrati
Organizations
- Loyola University New Orleans