title: 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.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center,  Houston, TX, USA.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Jung
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Se-Ran
authors.initials: SR
authors.lastname: Lee
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Kyounghyun
authors.initials: K
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000502:physiology; D011379:Prognosis; D014157:Transcription Factors / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D051858:Forkhead Transcription Factors; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D014157:Transcription Factors; C090140:Whn protein