Journal Article

FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair

Yun-Yong Park, Sung Yun Jung, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Guang Peng, Se-Ran Lee, Sang Bae Kim, Kyounghyun Kim, Sun-Hee Leem, Shiaw-Yih Lin, Gabriel Lopez-Berestein, Anil K. Sood and Ju-Seog Lee

in Carcinogenesis

Volume 33, issue 10, pages 1843-1853
Published in print October 2012 | ISSN: 0143-3334
Published online May 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs167
FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair

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  • Clinical Cytogenetics and Molecular Genetics

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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.

Journal Article.  5765 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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