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| Status |
Public on Nov 13, 2019 |
| Title |
ERα over-expression does not accelerate development of p53-deficient mammary tumors in mice [ChIP-Seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Binding of ERa in MCF7 cells and HA-tagged human ERa or HA-tagged mouse ERa in primary MMECs profiled by ChIP-seq (Chromatin Immunoprecipitation followed by deep sequencing).
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| Contributor(s) |
Cornelissen LM, Henneman L, Paulien Drenth A, Schut E, de Bruijn R, Zwart W, Jonkers J |
| Citation(s) |
31729597 |
| |
| Submission date |
Mar 05, 2019 |
| Last update date |
Feb 13, 2020 |
| Contact name |
Lisette Cornelissen |
| E-mail(s) |
l.cornelissen@nki.nl
|
| Organization name |
The Netherlands Cancer Institute
|
| Street address |
Plesmanlaan 121
|
| City |
Amsterdam |
| ZIP/Postal code |
1066 CX |
| Country |
Netherlands |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE127863 |
ERα over-expression does not accelerate development of p53-deficient mammary tumors in mice |
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| Relations |
| BioProject |
PRJNA525658 |
| SRA |
SRP187558 |
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