Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA376261 | ENA |
REPOSITORIES: ENA
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Project description:LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite roles remain largely elusive. By characterizing its role in normal and cancerous luminal mammary epithelial cells (MECs), here we show that LSD1 is essential for maintaining differentiation and survival of luminal cells. LSD1-inhibition by both genetic and pharmacological approaches increases invasion of luminal breast cancer cells. Mechanistically, we find LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression and represses that of TRIM37, a histone H2A ubiquitin ligase and breast cancer oncoprotein. LSD1-loss leads to reduced expression of several cell junction genes (e.g., CDH1, VCL, CTNNA1), possibly via TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the increased MEC invasiveness associated with LSD1-inhibition can be blocked via TRIM37-inhibition.
2019-08-16 | GSE95165 | GEO
Project description:The origin of breast cancer, whether primary or recurrent,is unknown. Here, we show that invasive breast cancer cells under conditions of hypoxia release small extracellular vesicles (sEV) that disrupt the differentiation hierarchy of the normal mammary epithelium, expand stem and luminal progenitor cells, and induce atypical ductal hyperplasia, cellular proliferation, and intraepithelial neoplasia. This is accompanied by systemic immunosuppression with increased myeloid cell release of the “alarmin”, S100A9, and multiple oncogenic traits of EMT, sustained angiogenesis, and local and disseminated luminal cell invasion, in vivo. When applied on the genetic background of a driver oncogene (MMTV-PyMT), hypoxic sEV accelerate bilateral breast cancer onset and progression. Mechanistically, genetic or pharmacologic targeting of hypoxia-inducible factor-1 (HIF1) packaged in hypoxic sEV or homozygous deletion of S100A9 normalizes mammary gland differentiation, restores T cell function and prevents atypical hyperplasia. The transcriptome of sEV-induced mammary gland lesions resembles luminal breast cancer, and detection of HIF1 in plasma circulating sEV from luminal breast cancer patients correlates with clinical recurrence. Therefore, a pleiotropic sEV-HIF1 signaling axis drives local and systemic mechanisms of mammary gland transformation at high risk for full-blown, multifocal breast cancer. This pathway may provide a readily accessible biomarker of luminal breast cancer progression.
2023-05-12 | GSE225986 | GEO
Project description:GATA-3 maintains luminal cell differentiation in the mammary gland and in breast cancer
| PRJNA96887 | ENA
Project description:Molecular subtypes of breast cancer are characterized by patterns of gene expression, which can be used to predict response to therapy and overall clinical outcome. The luminal breast cancer subtypes are defined by the expression of ER-alpha (ERa) and a set of ERa-associated genes. The transcription factor activator protein 2C (TFAP2C, AP-2C, AP-2g) transcription factor plays a critical role in regulating cell growth and differentiation during ectodermal development and has been implicated in the regulation of ERa and other luminal-associated genes in breast cancer. While TFAP2C has been established as a prognostic factor in human breast cancer, the role of TFAP2C in development of the luminal epithelial cells in the normal mammary gland and in breast cancer have remained elusive. Herein, we demonstrate a critical role of TFAP2C in maintaining the luminal differentiation phenotype during normal mammary development and in luminal breast carcinoma cell lines. Total RNA from MCF7 cells with and without knockdown of TFAP2c. 3 biological replicates, with 2 technical replicates each, were performed for each sample type.
2014-02-01 | E-GEOD-44203 | biostudies-arrayexpress
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
Project description:Molecular subtypes of breast cancer are characterized by patterns of gene expression, which can be used to predict response to therapy and overall clinical outcome. The luminal breast cancer subtypes are defined by the expression of ER-alpha (ERa) and a set of ERa-associated genes. The transcription factor activator protein 2C (TFAP2C, AP-2C, AP-2g) transcription factor plays a critical role in regulating cell growth and differentiation during ectodermal development and has been implicated in the regulation of ERa and other luminal-associated genes in breast cancer. While TFAP2C has been established as a prognostic factor in human breast cancer, the role of TFAP2C in development of the luminal epithelial cells in the normal mammary gland and in breast cancer have remained elusive. Herein, we demonstrate a critical role of TFAP2C in maintaining the luminal differentiation phenotype during normal mammary development and in luminal breast carcinoma cell lines.
2014-02-01 | GSE44203 | GEO
Project description:Emerging data indicate that breast epithelial stem cells and progenitors, particularly those in the luminal epithelial cell lineage, are the cells-of-origin of breast carcinomas, and factors that influence breast cancer risk may alter the number and/or properties of these cells. We hypothesize that a subset of p27+ cells represent hormone-responsive progenitors that are quiescent due to the high activity of TGFβ signaling in these cells. The Estrogen-induced mammary tumor model in ACI inbred rats is physiologically relevant rodent model of breast cancer. In the present study we successfully generated Cdkn1b knockout ACI rats and performed comprehensive phenotypic assessment and RNAseq profiling using FACS sorted basal (CD24+CD29high) and luminal (CD24+CD29low) cell populations to characterize Cdkn1b+/+ and Cdkn1b-/- females in prepubertal and adult cohorts. We found that p27KO rats exhibited mammary differentiation phenotype and reduced numbers of mammary epithelial progenitor pool, Interestingly, p27 ablation has the most pronounced effect on luminal progenitor cell gene expression, and milk protein genes and pStat5 were dramatically upregulated, while PR and FoxA1 were greatly downregulated in Cdkn1b-/- luminal cells. Further characterization of mammary glands of prepubertal Cdkn1b knockout rats by fat pad transplantation illustrated p27 deletion in the mammary cancer susceptible ACI rat strain induced mammary epithelial cell differentiation through cell non-autonomous mechanisms.
2019-02-11 | GSE116831 | GEO
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples
2012-05-29 | E-GEOD-28712 | 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 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:Background: Epithelial to mesenchymal transition (EMT) plays an essential role in the metastasis of breast cancer by regulating the migration and invasion of cancer cells. Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates EMT. However, the functional effects of the mutation on LSD1 in breast cancer remain unclear. Results: An E239K mutation of LSD1 was identified from TCGA Breast Invasive Carcinoma cohort. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with the wild-type LSD1, but not the E239K mutated LSD1, suppressed the increased invasion of the LSD1 knockdown cells, demonstrating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion of breast cancer cells. Further analysis showed that the E239K mutation of LSD1 led to decreased expression of estrogen receptor α (ERα), which subsequently increased the expression of Slug, a master transcription factor that promoted EMT. Most importantly, the E239K mutation of LSD1 disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of ERα gene. The reduced enrichment of LSD1 at the promoter region of ERα gene caused enhanced histone H3K9 methylation, which in turn suppressed the transcription of ERα gene. Conclusions: The E239K mutation of LSD1 promotes the migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3, which reduces the expression of ERα by enhancing the histone H3K9 methylation.
2021-03-12 | GSE168706 | GEO