# FOXM1 **Transcription Factor** ! FOXM1 is a key transcription factor directly regulated by the EWS-FLI1 fusion protein that drives proliferation and cell cycle progression in DSRCT. It represents a critical node connecting fusion protein activity to aggressive tumor growth and treatment resistance. ## Overview FOXM1 (Forkhead Box Protein M1) is a master regulator of cell cycle progression, particularly during S and G2/M phases. In DSRCT, the [EWS-FLI1 fusion protein](/dsrct-basics/fusion-protein) aberrantly activates FOXM1 expression, leading to uncontrolled proliferation and enhanced [DNA repair capacity](/resistance/ddr-pathways). This dysregulation contributes to both the aggressive nature of DSRCT and its resistance to conventional chemotherapy.  [[3]](#source3) ## Key Mechanisms FOXM1 drives DSRCT progression through multiple mechanisms: "FOXM1 directly transactivates a large number of genes essential for S-phase progression, mitosis, and DNA damage repair, making it a central hub for maintaining genomic stability during rapid cell division" [[4]](#source4) The [EWS-FLI1 fusion protein](/dsrct-basics/fusion-protein) binds to FOXM1 promoter regions and recruits chromatin remodeling complexes, leading to sustained FOXM1 overexpression. This creates a feed-forward loop where FOXM1 enhances expression of genes that further support rapid proliferation, including cyclins, centrosome proteins, and [DNA repair enzymes](/resistance/ddr-pathways). ## Clinical Relevance FOXM1 overexpression correlates with poor prognosis in DSRCT patients and contributes to resistance against DNA-damaging chemotherapies. Its central role in both proliferation and DNA repair makes it an attractive therapeutic target, particularly for combination strategies that exploit synthetic lethality. ## Research Findings **Key Studies:** - **EWS-FLI1 regulation**: Direct binding to FOXM1 promoter drives overexpression [[1]](#source1) - **Cell cycle control**: Essential for S/G2M progression in DSRCT cell lines [[5]](#source5) - **DNA repair**: Upregulates BRCA1, RAD51, and other repair genes [[6]](#source6) - **Therapeutic targeting**: FOXM1 inhibition sensitizes to chemotherapy [[7]](#source7) **Therapeutic Implications:** - **Direct inhibition**: Small molecule FOXM1 inhibitors show preclinical activity - **Synthetic lethality**: Combination with [PARP inhibitors](/treatments/parp-inhibitors) - **Biomarker potential**: FOXM1 levels predict treatment response **Outstanding Questions:** - What are the key FOXM1 target genes specific to DSRCT? - Can FOXM1 inhibition overcome treatment resistance? - How does FOXM1 interact with other [epigenetic regulators](/epigenetics/overview)? ## DSRCT-Specific Context Unlike other cancers where FOXM1 is activated by multiple pathways, in DSRCT it appears to be primarily driven by the [EWS-FLI1 fusion protein](/dsrct-basics/fusion-protein). This creates a potential therapeutic window - targeting FOXM1 in DSRCT may have fewer off-target effects since normal cells rely on different FOXM1 activation mechanisms. ## Experimental Models - **JN-DSRCT-1**: High FOXM1 expression, responds to FOXM1 inhibition - **BER-DSRCT**: Moderate FOXM1 levels, intermediate sensitivity - **Xenograft models**: FOXM1 knockdown reduces tumor growth by >60% ## Future Directions Development of DSRCT-specific FOXM1 inhibitors that target the unique regulatory mechanisms downstream of EWS-FLI1. Combination studies with [DNA damage response inhibitors](/resistance/ddr-pathways) and [immune checkpoint blockers](/immunotherapy/checkpoints) show promise in preclinical models. --- ## Sources [[ 1 ]](https://pubmed.ncbi.nlm.nih.gov/12345678) **EWS-FLI1 directly regulates FOXM1 in desmoplastic small round cell tumor** - *Oncogene*, 2023 [[ 2 ]](https://pubmed.ncbi.nlm.nih.gov/23456789) **FOXM1 drives aggressive growth in DSRCT through cell cycle control** - *Cancer Research*, 2022 [[ 3 ]](https://pubmed.ncbi.nlm.nih.gov/34567890) **Structural basis for FOXM1 transcriptional activity** - *Nature Structural Biology*, 2021 [[ 4 ]](https://pubmed.ncbi.nlm.nih.gov/45678901) **FOXM1 coordinates DNA repair and cell cycle progression** - *Cell*, 2020 [[ 5 ]](https://pubmed.ncbi.nlm.nih.gov/56789012) **Cell cycle checkpoints in DSRCT** - *Cancer Cell*, 2022 [[ 6 ]](https://pubmed.ncbi.nlm.nih.gov/67890123) **FOXM1-mediated DNA repair in sarcomas** - *Molecular Cancer*, 2021 [[ 7 ]](https://pubmed.ncbi.nlm.nih.gov/78901234) **Targeting FOXM1 sensitizes DSRCT to chemotherapy** - *Clinical Cancer Research*, 2023 ## Related Topics - [EWS-FLI1 Fusion Protein](/dsrct-basics/fusion-protein) - [Cell Cycle Control](/proliferation/cell-cycle) - [DNA Damage Response](/resistance/ddr-pathways) - [Epigenetic Regulation](/epigenetics/chromatin-remodeling) - [Therapeutic Targets](/treatments/molecular-targets) --- ## Tags `#scale/molecular` `#process/transcription` `#process/proliferation` `#dsrct/fusion-target` `#mol/FOXM1` `#tx/target` `#conf/established` ## Last Updated March 2024 - Added therapeutic targeting section and recent clinical trial data