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| Status |
Public on Jul 15, 2023 |
| Title |
Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways (RNA-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
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| Overall design |
To investigate the differentially expressed genes across EZH2 wildtype and knockout mouse strain during early tumor initiation phase, we cultured organoids obtained from mammary glands of both MIC/EZH2wt/wt and MIC/EZH2fl/fl mouse strains. These organoids were treated with doxycycline for a duration of 8 days to induce oncogene expresion (polyomavirus middle-T antigen) and deletion of conditional Ezh2 alleles. Following this, we harvested cells and extracted RNA. Subsequently, we subjected the RNA samples to RNA-sequencing analysis to analyze gene expression.
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| Contributor(s) |
Liu L, Pacis A |
| Citation(s) |
37549258 |
| |
| Submission date |
Jun 16, 2023 |
| Last update date |
Oct 13, 2023 |
| Contact name |
William Muller |
| E-mail(s) |
william.muller@mcgill.ca
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| Organization name |
McGill University
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| Department |
Biochemistry
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| Lab |
GCRC 507
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| Street address |
1160 Av des Pins O
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| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
H3A 1A3 |
| Country |
Canada |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE235147 |
Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways |
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| Relations |
| BioProject |
PRJNA984668 |
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