Similar Datasets
Project description:About 75% of all breast cancers express the nuclear hormone receptor oestrogen receptor α (ERα). However, the majority of mammary tumors from genetically engineered mouse models are ERα-negative. To model ERα-positive breast cancer in mice, we exogenously introduced expression of mouse and human ERα in an existing p53-deficiency driven breast cancer mouse model. After initial ERα expression during development of the mammary gland, expression was reduced or lost in adult glands and p53-deficient mammary tumors. ChIP-sequencing analysis of primary mouse mammary epithelial cells (MMECs) derived from these models, in which expression of the ERα constructs was induced in vitro, confirmed interaction of ERα with the DNA. In human breast and endometrial cancer, the pioneer factor FOXA1 is known to be essential to facilitate ERα/DNA binding. Surprisingly, the ERα binding sites identified in primary MMECs, but also in mouse mammary gland and uterus, showed a high enrichment of ERE motifs, but were devoid of Forkhead motifs. Furthermore, exogenous introduction of FOXA1 and GATA3 in ERα-expressing MMECs was not sufficient to promote ERα-responsiveness of these cells. Together, this suggests that species-specific differences in ERα-cistromes between mouse and human are dictated by the DNA sequence, resulting in ERα-dependencies in mice that are not FOXA1 driven and potentially not tumorigenic. These species-specific differences in ERα-biology can limit the use of mouse models in ERα-positive breast cancer research.
2019-11-13 | GSE127862 | GEO
Project description:About 75% of all breast cancers express the nuclear hormone receptor oestrogen receptor α (ERα). However, the majority of mammary tumors from genetically engineered mouse models are ERα-negative. To model ERα-positive breast cancer in mice, we exogenously introduced expression of mouse and human ERα in an existing p53-deficiency driven breast cancer mouse model. After initial ERα expression during development of the mammary gland, expression was reduced or lost in adult glands and p53-deficient mammary tumors. ChIP-sequencing analysis of primary mouse mammary epithelial cells (MMECs) derived from these models, in which expression of the ERα constructs was induced in vitro, confirmed interaction of ERα with the DNA. In human breast and endometrial cancer, the pioneer factor FOXA1 is known to be essential to facilitate ERα/DNA binding. Surprisingly, the ERα binding sites identified in primary MMECs, but also in mouse mammary gland and uterus, showed a high enrichment of ERE motifs, but were devoid of Forkhead motifs. Furthermore, exogenous introduction of FOXA1 and GATA3 in ERα-expressing MMECs was not sufficient to promote ERα-responsiveness of these cells. Together, this suggests that species-specific differences in ERα-cistromes between mouse and human are dictated by the DNA sequence, resulting in ERα-dependencies in mice that are not FOXA1 driven and potentially not tumorigenic. These species-specific differences in ERα-biology can limit the use of mouse models in ERα-positive breast cancer research.
2019-11-13 | GSE127859 | GEO
Project description:ERα over-expression does not accelerate development of p53-deficient mammary tumors in mice
| PRJNA525654 | ENA
Project description:ERα over-expression does not accelerate development of p53-deficient mammary tumors in mice [ChIP-Seq]
| PRJNA525658 | ENA
Project description:ERα over-expression does not accelerate development of p53-deficient mammary tumors in mice [RNA-Seq]
| PRJNA525659 | ENA
Project description: Not available
| S-EPMC4958311 | biostudies-literature
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.
2014-10-07 | GSE62101 | GEO
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.
2014-10-03 | GSE62016 | GEO
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
2014-10-07 | E-GEOD-62101 | biostudies-arrayexpress
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