FOXC1, the new player in the cancer sandbox

Elian, Fahed; Yan, Elizabeth; Walter, Michael A.

doi:10.18632/oncotarget.22742

Cited by 56 publications

(47 citation statements)

References 131 publications

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“…Along with the change in expression of fibronectin, our data suggest that FOXC1 may have a direct role in tissue/extracellular remodeling within the trabecular meshwork and could regulate the AH dynamics through the conventional outflow pathway as well. That FOXC1 has a role in ECM remodeling is unsurprising considering the vast amount of work done concerning FOXC1 in invasive cancers (reviewed in Elian et al 23 ). However, our result is contradictory to studies of FOXC1 in nasopharyngeal cancers, as studies show that reduced FOXC1 in nasopharyngeal cancers cells are associated with a decrease in MMP9.…”

Section: Discussionmentioning

confidence: 99%

FOXC1 Regulates Expression of Prostaglandin Receptors Leading to an Attenuated Response to Latanoprost

Doucette

Footz

Walter

2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. This study examines the effect of FOXC1 on the prostaglandin pathway in order to explore FOXC1's role in the prostaglandin-resistant glaucoma phenotype commonly seen in Axenfeld-Rieger syndrome.METHODS. Binding and transcriptional activity of FOXC1 to the gene coding for the EP3 prostaglandin receptor (PTGER3) were evaluated through ChIP-qPCR and luciferase-based assays. Immortalized trabecular meshwork cells (TM1) and HeLa cells had FOXC1 mRNA reduced via siRNA interference. qPCR and Western blot experiments were conducted to examine the changes in prostaglandin receptor expression brought about by lowered FOXC1. TM1 cells were then treated with 10 lM latanoprost acid and/or an siRNA for FOXC1. The expression of fibronectin and matrix metalloproteinase 9 were evaluated via qPCR in each treatment condition.RESULTS. ChIP-qPCR and luciferase experiments confirmed that FOXC1 binds to and activates transcription of the EP3 gene prostaglandin receptor. qPCR and Western experiments in HeLa and TM1 cells showed that FOXC1 siRNA knockdown results in significantly lowered EP3 levels (protein and RNA). In addition, RNA levels of the other prostaglandin receptor genes EP1 (PTGER1), EP2 (PTGER2), EP4 (PTGER4), and FP (PTGFR) were altered when FOXC1 was knocked down in TM1 and HeLa cells. Analysis of fibronectin expression in TM1 cells after treatment with 10 lM latanoprost acid showed a statistically significant increase in expression; this increase was abrogated by cotreatment with a siRNA for FOXC1. CONCLUSIONS.We show the abrogation of latanoprost signalling when FOXC1 is knocked down via siRNA in a trabecular meshwork cell line. We propose that the lower levels of active FOXC1 in Axenfeld-Rieger syndrome patients with glaucoma account for the lack of response to prostaglandin-based medications.Keywords: prostaglandins, Glaucoma, latanoprost, Axenfeld-Rieger, FOXC1 G laucoma is a leading cause of blindness in developed nations and is caused by the death of retinal ganglion cells within the retina. It has been predicted that 79.6 million people will be affected by glaucoma by the year 2020, 10% of whom will be bilaterally blind.1 Risk factors for the development of glaucoma include corticosteroid use, smoking, age, and ethnicity.2 However, the major risk factor for glaucoma is an increase in intraocular pressure (IOP). Generation and maintenance of IOP occurs through aqueous humor (AH) flow. Outflow of AH occurs through two outflow facilities, conventional and uveoscleral, generating this IOP, which maintains the globular structure of the eye. As increased IOP is the major risk factor for developing glaucoma, it is also the primary target for medical intervention. To manage IOP, surgical or pharmaceutical interventions are employed to either increase AH outflow or to decrease the amount of AH produced. The most common treatment for glaucoma is the administration of prostaglandinbased medications to lower IOP through increasing flow via the uveoscleral outflow facility. This outflow occurs through the supraciliary...

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Section: Discussionmentioning

confidence: 99%

FOXC1 Regulates Expression of Prostaglandin Receptors Leading to an Attenuated Response to Latanoprost

Doucette

Footz

Walter

2018

Invest. Ophthalmol. Vis. Sci.

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“…The role of many TFs have been studied in basal-like breast cancer, including oncogenic drivers such as MYC (6), and other TFs that regulate pathways associated with basal-like phenotypes such as EN1 (7), GLI1 (8), NF-kB (9), HIF1a (10), TWIST1 (11), FOXC1 (12,13), AP-1 (14), GR (15)(16)(17)(18), STAT3 (19,20), and MAFK (21). Many of these TFs regulate important pathways in basal-like breast cancer and these TFs often regulate each other's expression (22,23).…”

Section: Introductionmentioning

confidence: 99%

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Conway

McDaniel

Graham

et al. 2019

Preprint

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Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor a (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breast cancer because ER is the master regulator of the luminal gene expression program.In contrast, it is unclear which transcription factors are responsible for driving the gene expression signature that defines basal-like triple negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype of the disease. This study utilized integrated analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. The results of this study indicate that glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions that are specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperate to regulate expression of hundreds of genes in the basallike gene expression signature and these downstream genes are associated with poor prognosis in patients.Furthermore, combination treatment with small molecule drugs that inhibit both transcription factors leads to synergistic decreases in cell proliferation in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple negative breast cancer through rational combination of STAT3 and GR inhibitors.) in the chromatin regions that were specifically open in basal-like tumors and closed in luminal tumors ( Figure 1E). While the enrichment for the GR motif is significant, it is lower than that of STAT3 and JUN/AP1, which is consistent with previous studies that suggest GR can be tethered to some enhancers through protein:protein interactions, rather than direct DNA binding(30). MEC, JMM, JMG, KPG, PGO, and SLP performed experiments. MEC and KEV performed analysis and wrote the manuscript. PY and JT provided reagents. DJB, BEW, and RMM provided expertise and feedback.

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“…In recent years, rapidly accumulating evidence implicates the role of FOXC1 in cancer. FOXC1 is expressed not only in breast cancer subtypes such as basal-like breast cancer (BLBC), but also in hepatocellular carcinoma (HCC), endometrial cancer, Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) [8][9][10][11][12]. Increased FOXC1 expression now appears to be linked to more aggressive cancer phenotypes in BLBC, HCC, HL, and NHL [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the likelihood of FOXC1 expression in early- and late-stage tumors

Kume

Shackour

2018

Oncotarget

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Background: Aberrations in the expression of the transcription factor forkhead box C1 (FOXC1) have been linked to a number of malignancies. Here, we characterized the relationship between FOXC1 and cancer progression by conducting a metaanalysis of studies that reported the frequency of FOXC1 expression in tumors of different stages (T1, T2, T3, T4). Materials and Method: Relevant articles were retrieved from the Medline database by searching for the terms "FOXC1" and "cancer"; then, the retrieved articles were reviewed individually, and studies that were of multivariate cohort design, evaluated FOXC1 expression via immunohistochemical staining, and assessed the relationship between FOXC1 expression and cancer T-stage were included in our meta-analysis. Results: Our search terms identified 128 studies, 5 of which met all inclusion criteria. A total of 850 tumor samples were evaluated in the 5 studies; 452 samples were from early-stage (T1-T2) tumors, and 398 were from late-stage (T3-T4) tumors. FOXC1 was expressed in 60.7% (516/850) of all samples, in 54.6% (247/452) of early-stage tumor samples, and in 67.5% (269/398) of late-stage tumor samples. When calculated relative to early-stage samples, the pooled risk for FOXC1 expression in late-stage samples was 1.238 (95% CI = 1.061-1.444, p = 0.007). Conclusions: The results from our meta-analysis of 5 studies indicate that FOXC1 is 23.8% more likely to be expressed in late-stage tumors than in early-stage tumors.

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FOXC1, the new player in the cancer sandbox

Cited by 56 publications

References 131 publications

FOXC1 Regulates Expression of Prostaglandin Receptors Leading to an Attenuated Response to Latanoprost

FOXC1 Regulates Expression of Prostaglandin Receptors Leading to an Attenuated Response to Latanoprost

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Meta-analysis of the likelihood of FOXC1 expression in early- and late-stage tumors

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