Microarray expression profiling of Runx1-null and wildtype mouse mammary epithelial cells
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PROVIDER: PRJNA205360 | ENA |
REPOSITORIES: ENA
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Project description:RUNX1 encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that Runx1 is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of Runx1 in MECs by MMTV-Cre led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by loss of either Trp53 or Rb1. Mechanistically RUNX1 represses Elf5, a master regulatory TF gene for alveolar cells, and activates Foxa1, a key mature luminal TF gene involved in the ER program. Collectively, our data identified a key regulator of the ER+ luminal lineage whose disruption may contribute to development of ER+ luminal breast cancer when under the background of either TP53 or RB1 loss. Thoracic and inguinal mammary glands from 3 MMTV-Cre;Runx1L/L;R26Y and 3 MMTV-Cre;Runx1+/+;R26Y adult virgin females were dissected out, minced and digested to single cell suspension. Runx1L is the floxed conditional knockout allele of Runx1. R26Y is a conditional YFP reporter that would be turned on upon Cre-mediated recombination. FACSaria machine was used to sort out the YFP-marked luminal epithelial cell population of each of these 6 mice. Total RNA was isolated with Qiagen RNeasy kit and subsequently amplified by Nugen V2 and applied to Affymetrix mouse genome 430 2.0 arrays.
2014-11-26 | E-GEOD-47375 | biostudies-arrayexpress
Project description:RUNX1 encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that Runx1 is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of Runx1 in MECs by MMTV-Cre led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by loss of either Trp53 or Rb1. Mechanistically RUNX1 represses Elf5, a master regulatory TF gene for alveolar cells, and activates Foxa1, a key mature luminal TF gene involved in the ER program. Collectively, our data identified a key regulator of the ER+ luminal lineage whose disruption may contribute to development of ER+ luminal breast cancer when under the background of either TP53 or RB1 loss.
2014-11-26 | GSE47375 | GEO
Project description:Genetic and epigenetic changes in mammary epithelial cells facilitate epithelial-to-mesenchymal transition (EMT) which leads to invasion and metastasis. RUNX1 is a phenotypic transcription factor pivotal for maintenance of mammary epithelial phenotype, whose loss leads to EMT. However, the mechanisms by which RUNX1 maintains mammary epithelial phenotype are not known. Here, we report RUNX1-mediated mitotic gene bookmarking as a key epigenetic mechanism through which RUNX1 stabilizes mammary epithelial phenotype by conveying regulatory information for cell proliferation, growth, and identity through successive cell divisions. Immunofluorescence microscopy and chromatin immunoprecipitation with high throughput sequencing of asynchronous, mitotic, and G1 MCF10A breast epithelial cells revealed RUNX1 association with target genes through interphase and mitosis. RUNX1 mitotically bookmarked both RNA Pol and II transcribed genes involved in proliferation, growth, and mammary epithelial phenotype maintenance. Inhibition of RUNX1 DNA binding by a specific small molecule inhibitor led to phenotypic changes, apoptosis, and differential expression of ribosomal RNA as well as protein coding genes (e.g. HES1 and H2AFX) and long non-coding RNA (e.g. NEAT1 and MALAT1) genes involved in cellular phenotype. Together these findings reveal a novel epigenetic regulatory role of RUNX1 in normal-like breast epithelial cells and demonstrate mitotic bookmarking target genes by RUNX1 is necessary to maintain breast epithelial phenotype. Disruption of RUNX1 bookmarking by a pharmacological inhibitor results in initiation of epithelial to mesenchymal transition, an essential first step in the onset of breast cancer.
2020-07-14 | GSE121370 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-11-26 | GSE47377 | GEO
Project description:The Runx1 transcription factor is essential for hematopoietic differentiation and mutations underlie various leukemias. Here we demonstrate a role for Runx1 in the MCF10 cell series model of breast cancer progression. The highest level of Runx1 that occurs in normal like mammary epithelial cells (MCF10A) is decreased in tumorigenic (MCF10AT1) and metastatic (MCF10CA1a) breast cancer cells. We show that depletion of Runx1 in MCF10A cells results in striking changes in cell morphology and induction of epithelial-mesenchymal transition (EMT) via several signaling pathways. Analyses of breast tumors and patient survival data reveal that loss of Runx1 is associated with poor prognosis and decreased survival. Re-expressing Runx1 in MCF10AT1 breast cancer cells restores the epithelial phenotype. These results identify a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT. These mechanisms suggest Runx1 levels in early stage tumors can be used as a prognostic indicator of tumor progression.
2017-04-17 | GSE85857 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-11-26 | E-GEOD-47377 | biostudies-arrayexpress
Project description:RNAseq expression of p53-null and p53-null/PLK2-null mammary tumors
| PRJNA731110 | ENA
Project description:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor-positive mammary tumors with incomplete penetrance and long latency. We studied the growth and development of the mammary glands in Stat1-null mice. Stat1-null MGs have faulty branching morphogenesis with abnormal terminal end buds. The Stat1-null MG also fails to sustain growth of 129S6/SvEv wild-type and null epithelium. These abnormalities are partially reversed by added progesterone and prolactin. Transplantation of wild-type bone-marrow into Stat1-null mice does not reverse the mammary gland developmental defects. Media conditioned by Stat1-null epithelium-cleared mammary fat pads does not stimulate epithelial proliferation whereas it is stimulated by conditioned media derived from either wild-type or progesterone and prolactin-treated Stat1-null epithelium-cleared mammary fat pads. Microarrays and multiplex cytokine protein assays showed that the mammary gland of Stat1-null mice had lower levels of growth factors that have been implicated in normal mammary gland growth and development. Transplanted Stat1-null tumors and their isolated cells also grow slower in Stat1-null mammary gland compared to wild-type recipient mammary gland. Stat1-null hosts responded to tumor transplants with granulocytic infiltrates while wild-type hosts show a mononuclear response. These studies demonstrate that growth of normal and neoplastic Stat1-null epithelium primarily depends on the hormonal milieu and factors, such as cytokines, from the mammary stroma.
2015-05-01 | GSE63025 | GEO
Project description:The goal of this study was to compare mRNA from mammary epithelial cells of 3 mammary-specific Nmi knockout FVB with corresponding wildtype control. This was performed to obtain clues to the signaling pathways that were impacted in the mammary epithelial cells upon knocking-out Nmi expression.
2018-05-09 | GSE104238 | GEO
Project description:Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli – eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.
2021-09-22 | GSE184481 | GEO