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GATA3 Reprograms Basal Breast Cancer Cells towards a Luminal Subtype and Inhibits Metastases through Suppression of Lysyl Oxidase

ABSTRACT: The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24249 | GEO | 2011/09/01

SECONDARY ACCESSION(S): PRJNA133051

REPOSITORIES: GEO

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GATA3 Reprograms Basal Breast Cancer Cells towards a Luminal Subtype and Inhibits Metastases through Suppression of Lysyl Oxidase

Project description:The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche. There are 2 samples sent in triplicates.

2011-08-31 | E-GEOD-24249 | biostudies-arrayexpress

Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

Project description:Lysyl oxidase (LOX) is an copper dependent amine oxidase enzyme involved in cross linking of collagens and elastins. Lysyl oxidase propeptide (LOX-PP) is 18 kDa region cleaved during maturation of LOX and its anti-tumorigenic role were studied in various cancers. The effect of LOX-PP overexpression in retinoblastoma cancer cells (Y79) using transient transfection of LOX-PP gene accessed for global gene deregulations. The analysis resulted in RB cancer cell death through deregulation of retinoblastoma in cancer, cell cycle, apoptosis, focal adhesion-PI3K-AKT signaling and DNA repair mechanism pathway. Further validations were done using RT-PCR and western blot analysis. Our results provide evidence that inducing apoptosis through AKT-NFκB signaling.

2019-09-01 | GSE119413 | GEO

Comparison of GATA3 mutant and GATA3 wild type isogenic MCF-7 and CAMA1 breast cancer cell lines

Project description:The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, largely frameshifting, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes upregulated and downregulated in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein.

2018-01-12 | GSE101780 | GEO

The¬¬¬ androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.

2024-01-30 | PXD047997 | Pride

A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

2023-05-18 | GSE186748 | GEO

GATA3/G9A/MTA3 sequencing in non-treated MCF-7 cells

Project description:Transcription factor GATA3 is essential for the specification and maintenance of the luminal cell differentiation in the mammary gland, and its expression is progressively lost during luminal breast cancer progression. However, how loss-of-function of GATA3 contributes to the development of breast cancer is still poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes that are critically involved in epithelial-to-mesenchymal transition and cell invasion.

2015-03-25 | GSE67206 | GEO

Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

Project description:Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

| PRJNA489199 | ENA

Effect of GATA3 suppression gene expression in breast cancer cells.

Project description:Neoadjuvant chemotherapy (NAC) is the major pre-treatment for breast cancer before surgery. Patients who achieve pathologic complete response (pCR) have a higher chance to receive lumpectomy and a better quality of life after neoadjuvant treatment. Luminal subtype breast cancer has poor NAC response compared with triple-negative breast cancer (TNBC) subtype. The molecular and cellular mechanisms underlying this chemoresistance are not fully understood. Here we report that the 17 featured transcriptional factors (TFs) in luminal and TNBC were identified. The association between 17 TFs and NAC pCR were analysis and exogenous luminal featured TF GATA3 overexpression promotes chemotherapy resistance in TNBC cell lines whereas its knockdown promotes sensitivity. In mechanism, we found that anthracycline based chemotherapy induces robust cellular ROS and Fe2+ overload in sensitivity cells; GATA3 mediates cell survival through repress CYB5R2 expression and Fenton reducing in DOX recycle which reduce cellular ROS and Fe2+ level during chemotherapy procedure. These founding altogether indicate that luminal featured transcription factor GATA3 enhance NAC resistance thorough repress ROS production and Fenton reducing. Breast cancer patient with GATA3 high expression might not suit for anthracycline based NAC regimen.

2023-01-01 | GSE216413 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive_PDX_GATA3_ChIP-seq]

Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.

2023-12-21 | GSE178254 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive_cell_line_GATA3_ChIP-seq]

2023-12-21 | GSE178253 | GEO

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