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Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer

ABSTRACT: Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer

PROVIDER: PRJNA775059 | ENA |

REPOSITORIES: ENA

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Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer II

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

Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer I

2021-12-14 | GSE186679 | GEO

Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer I

Project description:Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer I

| PRJNA775056 | ENA

Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer II

Project description:Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer II

| PRJNA775066 | ENA

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer.

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

Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-14 | GSE186683 | GEO

Suppression of the FOXM1 transcriptional program via novel small molecule inhibition

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

RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

Project description:RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

| PRJNA860213 | ENA

FOXM1-AKT positive regulation loop provides venetoclax resistance in AML

Project description:FOXM1 and AKT are crucial pro-oncogenic regulators of cancer therapy resistance. Due to reciprocal regulatory links they establish a positive feedback autoregulation loop in AML cells. Disruption of this loop via inhibition of either FOXM1 or AKT results in similar gene expression changes, drastic upregulation of HOXA genes and sensitization of AML cells to cytarabine and venetoclax treatment.

2021-08-18 | GSE172189 | GEO

STL427944 suppresses FOXM1 via nuclear export and subsequent autophagic degradation

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

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