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Microarray expression profiling data for Trp53/Brca1-null mammary tumors derived from K8+ luminal cells

ABSTRACT: BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE114787 | GEO | 2019/06/27

REPOSITORIES: GEO

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RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells with a K8+ luminal origin

Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre one month after the intraductal injection.

2019-06-27 | GSE126761 | GEO

Single cell RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells and tumor cells with a K8+ luminal origin

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RNAseq of mouse mammary luminal cells

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aCGH data of Rb/p53 deficient mammary tumors

Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used aCGH to detect copy number alterations associated with Rb/p53 deletion. Tumor DNAs from MMTV-Cre: Rbf/f;p53f/f and Ad-Cre: Rbf/f;p53f/f conditional mutant mice are being compared to pooled tail DNAs in order to identify common alterations associated with Rb/p53 deficient tumorigenesis

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Microarray expression profiling study of Runx1-null and wild type luminal mammary epithelial cells

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

Expression data comparing Rb/p53 and p53 deficient mammary tumors and normal mammary tissue

Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used microarrays to detect differentially expressed genes in the Rb/p53 double-knock-out vs p53 single deletion or normal mammary tissue. Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays

2014-10-03 | E-GEOD-62016 | biostudies-arrayexpress

Expression data comparing Rb/p53 and p53 deficient mammary tumors and normal mammary tissue

Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used microarrays to detect differentially expressed genes in the Rb/p53 double-knock-out vs p53 single deletion or normal mammary tissue.

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aCGH data of Rb/p53 deficient mammary tumors

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Transcription profiling by array of mouse mammary epithelial stem cell tumours.

Project description:The aim of the experiment was to analyse gene expression profiles in Brca1 tumours arising from different mammary epithelial cell populations use a Cre-loxP based conditional knockout system. K14 promoter driving Cre expression caused Brca1 knockout in basal stem cells and thus stem cell origin tumours whereas Blg promoter driving Cre expression caused Brca1 knockout in luminal progenitor cells and thus progenitor origin tumours. Individual arrays were carried out on labelled cDNA made from RNA isolated from mouse mammary tumours. Only cDNA passing Almac diagnostics QC criteria were hybridised to arrays. Only arrays passing QC criteria after hybrisiation were subsequently analysed.

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