Transcriptional Repression by FoxM1 Suppresses Tumor Differentiation and Promotes Metastasis of Breast Cancer

Kopanja, Dragana; Chand, Vaibhav; O'Brien, Eilidh; Mukhopadhyay, Nishit K.; Zappia, María Paula; Islam, Abul B.M.M.K.; Frolov, Maxim V.; Merrill, Bradley J.; Raychaudhuri, Pradip

doi:10.1158/0008-5472.can-22-0410

Cited by 23 publications

(20 citation statements)

References 55 publications

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“…For example, the selective estrogen receptor degraders (SERDs), such as fulvestrant ( 76 ), bind to ERα and induce structural changes that result in its proteosome-mediated degradation. Importantly, FOXM1 acts as both a transcriptional activator and a repressor, with the latter activity recently shown to support metastatic progression in a model of luminal B breast cancer ( 77 ). Induced degradation of FOXM1 is therefore an attractive strategy, as it would interfere with both aspects of FOXM1 function.…”

Section: Discussionmentioning

confidence: 99%

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Nandi¹,

Smith²,

Sanguin-Gendreau³

et al. 2023

Journal of Clinical Investigation

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Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcome, yet the underlying mechanisms are incompletely understood. Here, we have shown that deleting c-Src in a genetically engineered model mimicking the Luminal B molecular subtype of breast cancer abrogates the activity of Forkhead Box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylates FOXM1 on two tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2-M cell cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of Luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2-M cell cycle arrest and apoptosis, blocked tumor progression and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and showed that the expression of FOXM1 target genes predicts poor outcome and associates with the Luminal B subtype, which responds poorly to approved therapies. These findings have revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.

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Section: Discussionmentioning

confidence: 99%

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Nandi¹,

Smith²,

Sanguin-Gendreau³

et al. 2023

Journal of Clinical Investigation

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“…32 FOXM1-Rb complex downregulates luminal differentiation gene FOXA1, mammary differentiation gene Gata3, and tumor suppressor Pten in breast cancer cells. 32,33 The correlation between FOXM1 and the estradiol signaling pathway has been studied in breast cancer. 34 FOXM1 can activate the transcriptional activity of the ERα promoter via interaction with the coactivator CARM1.…”

Section: Discussionmentioning

confidence: 99%

The PES1/FOXM1 heterodimer suppresses TCF21 and ERβ expression in ovarian endometriosis

Zhu,

Wu,

et al. 2023

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Transcription factor 21 (TCF21) and estrogen receptor beta (ERβ, encoded by ESR2) are highly expressed in endometriotic stromal cells (ESCs) and contribute to the pathogenesis of endometriosis. However, the exploration of TCF21 and ERβ expression regulation at the molecular level remains limited. Here, by using bioinformatics analysis and experimental verification, we identified PES1, also known as Pescadillo, as a negative regulator in the development of endometriosis that downregulates TCF21 and ERβ expression in ESCs. PES1 overexpression regulated critical biological processes involved in endometriosis development, such as invasion and apoptosis. A coimmunoprecipitation assay showed that PES1 could form a complex with Forkhead box M1 (FOXM1). Further analyses elucidated that siPES1 in ectopic lesions decreased the stability of FOXM1 protein and reduced the binding activities of FOXM1 to TCF21 and ESR2 promoters, thus weakening the transcriptional inhibition of TCF21 and ERβ by FOXM1. Moreover, in an endometriosis mouse model, overexpressing PES1 effectively reduced the growth of ectopic lesions and suppressed TCF21 and ERβ expression, which suggests a promising therapeutic strategy for endometriosis. Collectively, our results indicate that the loss of PES1 in ectopic lesions contributes to endometriosis progression by upregulating ERβ and TCF21 expression through heterodimer formation with FOXM1. Moreover, targeting PES1 could serve as a treatment method for endometriosis.

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“…FOXM1 ranks among the most diferentially expressed genes. In this study, we focus on FOXM1 because it is involved in cancer stemness and metastasis [27][28][29]. Dysfunction of FOXM1 occurs in several malignant cancers and is highly correlated with poor prognosis and enhanced metastasis [13][14][15].…”

Section: Discussionmentioning

confidence: 99%

Sequential Treatment with Activin and Hepatocyte Growth Factor Induces FOXM1 to Promote Colorectal Cancer Liver Metastasis

Peng

Deng

et al. 2022

Canadian Journal of Gastroenterology and Hepatology

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Background. Cancer stem cells (CSCs) are involved in liver metastasis in colorectal cancer (CRC). Activin and hepatocyte growth factor (HGF) are important regulators of stem cell properties. This study was performed to explore the effect of activin and HGF on CRC invasion and metastasis. The key genes involved in the action of activin and HGF in CRC were identified. Methods. HCT116 CRC cells were sequentially treated with activin and HGF and examined for migration and invasion in vitro and liver metastasis in vivo. RNA sequencing was performed to identify differentially expressed genes in response to activin and HGF. Results. Sequential treatment with activin and HGF-enhanced CRC cell migration, invasion, and metastasis. CXCR4 and AFP expressions were increased by activin and HGF treatment. Knockdown of FOXM1 blocked liver metastasis from HCT116 cells pretreated with activin and HGF and suppressed CXCR4 and AFP expression. Activin alone increased the mRNA and protein expression of FOXM1. In contrast, HGF alone enhanced the phosphorylation of FOXM1, without altering the total protein level of FOXM1. SMAD2 was required for activin-mediated FOXM1 induction. FOXM1 transactivated CXCR4 by directly binding to the promoter of CXCR4. Additionally, CXCR4 regulated AFP expression through the NF-κB pathway. Conclusions. Sequential treatment with activin and HGF accelerates CRC invasion and liver metastasis, which involves the upregulation and activation of FOXM1 and induction of CXCR4 and AFP.

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Transcriptional Repression by FoxM1 Suppresses Tumor Differentiation and Promotes Metastasis of Breast Cancer

Cited by 23 publications

References 55 publications

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

The PES1/FOXM1 heterodimer suppresses TCF21 and ERβ expression in ovarian endometriosis

Sequential Treatment with Activin and Hepatocyte Growth Factor Induces FOXM1 to Promote Colorectal Cancer Liver Metastasis

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