期刊
CARCINOGENESIS
卷 33, 期 10, 页码 1843-1853出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgs167
关键词
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类别
资金
- intramural faculty fund of The University of Texas MD Anderson Cancer Center
- MEST of Korea [2011-0001047]
- Shared Research Equipment Assistance
- National Institutes of Health [RC2GM092599, U54 CA151668, CA128797]
- Department of Defense [BC085265]
- National Institutes of Health through Cancer Center Support Grant [CA016672]
- Basic Science Research Program through the National Research Foundation [2011-0001047]
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 NFB1 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.
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