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FOXD1 is associated with poor outcome and maintains tumor-promoting enhancer-gene programs in basal-like breast cancer [RNA-seq]

ABSTRACT: Breast cancer biology varies markedly among patients. Basal-like breast cancer is one of the most challenging subtypes to treat because it lacks effective therapeutic targets. Despite numerous studies on potential targetable molecules in this subtype, few targets have shown promise. However, the present study revealed that FOXD1, a transcription factor that functions in both normal development and malignancy, is associated with poor prognosis in basal-like breast cancer. We analyzed publicly available RNA sequencing data and conducted FOXD1-knockdown experiments, finding that FOXD1 maintains gene expression programs that contribute to tumor progression. We first conducted survival analysis of patients grouped via a Gaussian mixture model based on gene expression in basal-like tumors, finding that FOXD1 is a prognostic factor specific to this subtype. Furthermore, our RNA sequencing and chromatin immunoprecipitation sequencing experiments on the basal-like breast cancer cell lines BT549 and Hs578T with FOXD1 knockdown revealed that FOXD1 regulates enhancer-gene programs related to tumor progression. These findings suggest that FOXD1 plays an important role in basal-like breast cancer progression and may represent a promising therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230118 | GEO | 2023/04/25

REPOSITORIES: GEO

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FOXD1 is associated with poor outcome and maintains tumor-promoting enhancer-gene programs in basal-like breast cancer [ChIP-seq]

Project description:Breast cancer biology varies markedly among patients. Basal-like breast cancer is one of the most challenging subtypes to treat because it lacks effective therapeutic targets. Despite numerous studies on potential targetable molecules in this subtype, few targets have shown promise. However, the present study revealed that FOXD1, a transcription factor that functions in both normal development and malignancy, is associated with poor prognosis in basal-like breast cancer. We analyzed publicly available RNA sequencing data and conducted FOXD1-knockdown experiments, finding that FOXD1 maintains gene expression programs that contribute to tumor progression. We first conducted survival analysis of patients grouped via a Gaussian mixture model based on gene expression in basal-like tumors, finding that FOXD1 is a prognostic factor specific to this subtype. Furthermore, our RNA sequencing and chromatin immunoprecipitation sequencing experiments on the basal-like breast cancer cell lines BT549 and Hs578T with FOXD1 knockdown revealed that FOXD1 regulates enhancer-gene programs related to tumor progression. These findings suggest that FOXD1 plays an important role in basal-like breast cancer progression and may represent a promising therapeutic target.

2023-04-25 | GSE230117 | GEO

Gene expression profile in breast cancer cell lines using RNA sequencing

Project description:In order to identify novel molecular targets associated with TNBC progression, we initially performed transcriptome analysis using RNA sequencing in breast cancer cell lines, classified as either the luminal subtype (MCF-7, T47D, ZR-75B) or basal-like subtype (MDA-MB-231, MDA-MB-435, Hs578T).

2017-08-09 | GSE100878 | GEO

Effect of Foxd1 knockdown in the reprogramming process

Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) of Foxd1+/+, Foxd1+/- or Foxd1-/- were infected with retroviruses encoding the three transcription factors (Oct4, Sox2 and Klf4) at day 0 and sampled at day 8.

2014-01-11 | E-GEOD-51179 | biostudies-arrayexpress

Effect of Foxd1 knockdown in the reprogramming process

2014-01-11 | GSE51179 | GEO

Gene expression comparison of E14.5 Foxd1 null and wild type kidneys

Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type. Embryonic kidneys were harvested from Foxd1-/- and wild type littermates from three E14.5 litters. Three biological replicates were generated per genotype, each containing two non-littermate kidney pairs. Sex of embryos was not determined.

2013-11-14 | E-GEOD-52354 | biostudies-arrayexpress

Gene expression comparison of E14.5 Foxd1 null and wild type kidneys

2013-11-14 | GSE52354 | GEO

Upregulation of FOXD1 by YAP alleviates senescence and osteoarthritis

Project description:Cell senescence is a driver of various aging-associated disorders including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (MSCs) and ameliorating osteoarthritis in mice. Targeted knockout of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP interacted with TEA domain transcriptional factor (TEAD) to activate forkhead box D1 (FOXD1) expression. YAP deficiency led to the downregulation of FOXD1, a geroprotective protein. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vectors encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential therapeutic target for gene therapy to alleviate osteoarthritis.

2019-02-17 | GSE110268 | GEO

FOXD1 Promotes Dedifferentiation and Vemurafenib-resistance in Melanoma by Regulating the Expression of CTGF

Project description:Metastatic melanoma is the most aggressive skin cancer and associated with a poor prognosis. Targeted therapy is one of the most important treatments for patients with BRAFV600E-mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. Increasing evidence has indicated that NC-associated genes play important roles in tumor progress and drug resistance. Our previous study showed that FOXD1 is a neural crest (NC)-associated gene that has high expression levels both in NC cells and melanoma and that it could regulate melanoma migration and invasion. Here, we found that the FOXD1-CTGF axis is important for melanoma resistance. The connective tissue growth factor (CTGF) was identified as a direct downstream factor of FOXD1 using microarray assay. In detail, when we compared the microarray data from FOXD1 OE and control groups, we found that the expression level of CTGF was also higher in FOXD1 OE cells (FC=1.97).

2021-03-29 | GSE162973 | GEO

Targets for renal carcinoma growth control identified by screening FOXD1 cell proliferation pathways

Project description:FOXD1 regulates proliferation of clear cell renal cell carcinoma (ccRCC) cells, and ccRCC cells in which FOXD1 has been inactivated do not form tumors efficiently in an animal model. Reproducing growth inhibition in tumor cells by inhibiting FOXD1 pathways presents an possible therapeutic approach for ccRCC and other cancers. We have established an analysis strategy to identify FOXD1-regulated target pathways that may be therapeutically tractable and compounds that modulate these pathways were selected for testing.

2022-08-01 | GSE210145 | GEO

Gene expression profiling of E18.5 FoxD1 Cre;Dicer and control embryonic kidneys

Project description:The aim of this study is to address the functional role of miRNAs in the FoxD1+ renal stroma progenitors and derivatives during embryonic kidney development. To achieve this, we generated transgenic mice that lack miRNAs in the renal stroma lineage (FoxD1 Cre;Dicer), and performed a microarray analysis on E18.5 whole kidneys to determine the transcriptional changes. 3 litters of E18.5 FoxD1 Cre;Dicer and control littermate kidneys were used for the microarray analysis. Each litter consists of kidneys pooled from 2 embryos per genotype for the RNA extraction.

2015-11-04 | E-GEOD-64441 | biostudies-arrayexpress

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