FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
Abstract
Transcription factors are direct effectors of altered signaling pathways in cancer and frequently determine clinical outcomes in cancer patients. To uncover new transcription factors that would determine clinical outcomes in breast cancer, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that Forkhead box protein M1 (FOXM1) is the top-ranked survival-associated transcription factor in patients with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NFκB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in breast cancer cells in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes, and our findings provide mechanistic insights into how FOXM1 mediates resistance to Dox and evidence that FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 10, 2012
- Source ID
- 10.1093/carcin/bgs167
Entities
People
- Anil K. Sood
- Cristian Rodriguez-Aguayo
- Gabriel Lopez-berestein
- Guang Peng
- Ju-Seog Lee
- Kyounghyun Kim
- Nicholas B. Jennings
- Sang Bae Kim
- Se-ran Lee
- Shiaw-Yih Lin
- Sun-hee Leem
- Sung Yun Jung
- Yun-yong Park
Organizations
- Baylor College of Medicine
- Dong-A University
- National Institutes of Health
- Texas A&M University
- United States Department of Defense
- University of Texas at Austin