Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA157129 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a M-bM-^@M-^\bi-lineageM-bM-^@M-^] differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition. Total of four treatments (HCC70 cells stably expressing shEZH2, shEED, or EZH2 cDNA, and MDA-MB-468 cells stably expressing shEZH2) were done in duplicates, each with its own control.
2012-09-21 | E-GEOD-36939 | biostudies-arrayexpress
Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a “bi-lineage” differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.
2012-09-21 | GSE36939 | GEO
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively:CD44+/CD24-,Basal B (G4, H6) cells and CD44hi/CD24lo epithelioid Basal A (A4, AB) cells. Seven replicates of A4, seven replicates of G4, three replicates of AB, three replicates of H6
2015-04-30 | E-GEOD-59281 | biostudies-arrayexpress
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively:CD44+/CD24-,Basal B (G4, H6) cells and CD44hi/CD24lo epithelioid Basal A (A4, AB) cells.
2015-04-30 | GSE59281 | GEO
Project description:Both EZH2 and NF-?B contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-?B target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-?B targets. Intriguingly, EZH2 acts oppositely in repressing NF-?B targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-?B targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers. 12 samples were analyzed including three replicates of siNC CTRL and siEZH2 CTRL.
2011-08-14 | E-GEOD-30670 | biostudies-arrayexpress
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned two CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively. Rather than CD44+/CD24-,Basal B (G4) cells, only CD44hi/CD24lo, epithelioid Basal A (A4) cells retained a tumor-initiating capacity in NOG mice, form mammospheres and exhibit resistance to standard chemotherapy. Microarray data obtained from Affymetrix Human Gene 1.0 ST Array Five replicates of A4 and 5 replicates of G4
2012-06-11 | E-GEOD-32455 | biostudies-arrayexpress
Project description:Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in repressing NF-κB targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-κB targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.
2011-08-15 | GSE30670 | GEO
Project description:The CD44hi compartment in human breast cancer is enriched in tumor-initiating cells, however the functional heterogeneity within this subpopulation remains poorly defined. From a human breast cancer cell line with a known bi-lineage phenotype we have isolated and cloned two CD44hi populations that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively. Rather than CD44+/CD24-,Basal B (G4) cells, only CD44hi/CD24lo, epithelioid Basal A (A4) cells retained a tumor-initiating capacity in NOG mice, form mammospheres and exhibit resistance to standard chemotherapy. Microarray data obtained from Affymetrix Human Gene 1.0 ST Array
2012-06-12 | GSE32455 | GEO
Project description:Breast cancer remains a leading cause of death among women, encompassing diverse molecular subtypes with distinct clinical outcomes. The HER2+ subtype is particularly aggressive, with many patients eventually developing resistance to HER2-targeted therapies, underscoring the urgent need for alternative treatment strategies. Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, represses the expression of genetic programs crucial for differentiation, control of proliferation, and apoptosis through histone H3 lysine 27 trimethylation (H3K27me3). To investigate the role of EZH2 in HER2+ tumor progression, we crossed a genetically engineered mouse model (GEMM) of HER2-driven breast cancer with a conditional Ezh2 knockout strain. The results showed that Ezh2 is essential for accelerating tumor initiation and metastatic dissemination in HER2-driven breast cancer. Combined bulk and single cell RNA sequencing analyses revealed a significant downregulation of basal cell populations in the absence of Ezh2, characterized by the loss of Tp63 expression, and an upregulation of luminal progenitor cell populations, driven by crucial transcription factors such as Esr1, thereby driving luminal lineage commitment. Further, inhibition of EZH2 in vitro resulted in increased expression of ER in HER2+ human breast cancer cell lines and rendered them susceptible to tamoxifen. Altogether, these findings demonstrate that EZH2 dictates breast cancer plasticity through control of cellular identity and provides rationale for combining EZH2 inhibitors with endocrine therapies to improve outcomes in HER2+ breast cancer.
2025-10-28 | GSE303527 | GEO
Project description:Breast cancer remains a leading cause of death among women, encompassing diverse molecular subtypes with distinct clinical outcomes. The HER2+ subtype is particularly aggressive, with many patients eventually developing resistance to HER2-targeted therapies, underscoring the urgent need for alternative treatment strategies. Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, represses the expression of genetic programs crucial for differentiation, control of proliferation, and apoptosis through histone H3 lysine 27 trimethylation (H3K27me3). To investigate the role of EZH2 in HER2+ tumor progression, we crossed a genetically engineered mouse model (GEMM) of HER2-driven breast cancer with a conditional Ezh2 knockout strain. The results showed that Ezh2 is essential for accelerating tumor initiation and metastatic dissemination in HER2-driven breast cancer. Combined bulk and single cell RNA sequencing analyses revealed a significant downregulation of basal cell populations in the absence of Ezh2, characterized by the loss of Tp63 expression, and an upregulation of luminal progenitor cell populations, driven by crucial transcription factors such as Esr1, thereby driving luminal lineage commitment. Further, inhibition of EZH2 in vitro resulted in increased expression of ER in HER2+ human breast cancer cell lines and rendered them susceptible to tamoxifen. Altogether, these findings demonstrate that EZH2 dictates breast cancer plasticity through control of cellular identity and provides rationale for combining EZH2 inhibitors with endocrine therapies to improve outcomes in HER2+ breast cancer.
2025-11-07 | GSE303503 | GEO