Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer II
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ABSTRACT:
PROVIDER: PRJNA775066 | ENA |
REPOSITORIES: ENA
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Project description:Forkhead box M1 (FOXM1) is an oncogenic transcription factor overexpressed in many cancers and associated with aggressiveness. Using 1,1-diarylethylene-diammonium compounds that suppress FOXM1 activity, we utilized genome-wide transcriptomic, protein analyses, and functional approaches to identify mechanisms by which these compounds inhibit breast cancer growth and survival. These compounds downregulated FOXM1 gene networks in estrogen receptor (ER)-positive and triple negative breast cancer (TNBC) cells, and RNA-Seq and pathway analyses revealed that cell cycle progression, DNA damage repair, and apoptosis were most greatly affected, in agreement with the cancer promoting functions of FOXM1. TNBC and ER-positive breast cancer cells grown long-term with the inhibitors developed resistance. Notably, resistant cells showed transcriptional alterations and rewiring leading to reversal of the regulation of many genes in the FOXM1 network and marked changes in inflammatory signaling and HER2 and EGFR signature genes and pathways. High expression of a 43-gene Interferon-Related FOXM1 inhibitor resistance Signature (IRFMS) derived from ER-positive inhibitor resistant cells predicted a less good prognosis and poorer survival in patients with ER-positive breast cancer. Resistant cells showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefit and enable prolonged anticancer effectiveness.
2021-12-14 | GSE186682 | GEO
Project description:Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer
| PRJNA775059 | ENA
Project description:Forkhead box M1 (FOXM1) is an oncogenic transcription factor overexpressed in many cancers and associated with aggressiveness. Using 1,1-diarylethylene-diammonium compounds that suppress FOXM1 activity, we utilized genome-wide transcriptomic, protein analyses, and functional approaches to identify mechanisms by which these compounds inhibit breast cancer growth and survival. These compounds downregulated FOXM1 gene networks in estrogen receptor (ER)-positive and triple negative breast cancer (TNBC) cells, and RNA-Seq and pathway analyses revealed that cell cycle progression, DNA damage repair, and apoptosis were most greatly affected, in agreement with the cancer promoting functions of FOXM1. TNBC and ER-positive breast cancer cells grown long-term with the inhibitors developed resistance. Notably, resistant cells showed transcriptional alterations and rewiring leading to reversal of the regulation of many genes in the FOXM1 network and marked changes in inflammatory signaling and HER2 and EGFR signature genes and pathways. High expression of a 43-gene Interferon-Related FOXM1 inhibitor resistance Signature (IRFMS) derived from ER-positive inhibitor resistant cells predicted a less good prognosis and poorer survival in patients with ER-positive breast cancer. Resistant cells showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefit and enable prolonged anticancer effectiveness.
2021-12-14 | GSE186679 | GEO
Project description:Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer I
| PRJNA775056 | ENA
Project description:Forkhead box M1 (FOXM1), an oncogenic transcription factor associated with aggressiveness and highly expressed in many cancers, is an emerging therapeutic target. Using novel 1,1-diarylethylene-diammonium small molecule FOXM1 inhibitors, we undertook transcriptomic, protein, and functional analyses to identify mechanisms by which these compounds impact breast cancer growth and survival, and the changes that occur in estrogen receptor (ERα)-positive and triple negative breast cancer cells that acquire resistance upon long-term treatment with the inhibitors. In sensitive cells, these compounds regulated FOXM1 gene networks controlling cell cycle progression, DNA damage repair, and apoptosis. Resistant cells showed transcriptional alterations that reversed the expression of many genes in the FOXM1 network and rewiring that enhanced inflammatory signaling and upregulated HER2 or EGFR growth factor pathways. ERα-positive breast cancer cells that developed resistance showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefits and prolong anticancer effectiveness. Improved understanding of how FOXM1 inhibitors suppress breast cancer and how cancer cells can defeat their effectiveness and acquire resistance should be helpful in directing further studies to move these agents towards translation into the clinic.
| S-EPMC8699539 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-14 | GSE186683 | GEO
Project description:The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA binding domain (DBD), and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Herein we identify novel inhibitors of FOXM1 that block DNA binding from a high-throughput screen applied to a library of 54,211 small molecules. One compound, FDI-6 (NCGC00099374) is studied in depth and is shown to bind directly to FOXM1 protein, displace the transcription factor from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional down-regulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically down regulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-seq. This small molecule mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors.
2014-08-15 | GSE58626 | GEO
Project description:RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design
| PRJNA860213 | ENA
Project description:FOXM1 transcription factor is an oncogene and a crucial regulator of cancer chemoresistance. Existing pharmacological FOXM1 inhibitors attenuate resistance of cancer cells to treatment but exhibit insufficient specificity. We performed in silico screening of small molecules from NIH LINCS database to identify STL427944 compound that suppresses FOXM1 through a novel two-step mechanism. STL427944 treatment induces relocalization of nuclear FOXM1 protein to cytoplasm, where it is subsequently degraded in an autophagosome-dependent manner. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic agents. Transcriptome-based analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 towards FOXM1. We expect that STL427944 or its derivatives may be used in combination with different chemotherapeutical drugs to overcome tumor chemoresistance and improve anti-cancer treatment efficacy.
2021-07-21 | GSE162826 | GEO
Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
2024-03-10 | PXD050300 | Pride