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| Status |
Public on Jul 10, 2024 |
| Title |
CCN6/WISP3 suppresses metaplastic breast carcinoma by antagonizing a WNT/b-catenin/EZH2 cascade [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation, including varied non-glandular features. CCN6/WISP3 tumor suppressor gene inactivation and b-catenin-dependent Wnt pathway activation are often seen in mBrCAs. We have reported MMTV-Cre;Ccn6fl/fl (Ccn6-KO) mice develop spindle mBrCAs with EMT and elevated expression of the Wnt/b-catenin pathway genes HMGA2 and IGF2BP2. The mechanisms by which the secreted CCN6 protein exerts tumor suppressor functions in breast tissues are uncertain. Here, we show recombinant CCN6 protein interacts with Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt ligand-mediated activation of b-catenin/T-cell-factor (TCF) transcription. We identify the gene for histone methyltransferase EZH2, the catalytic component of polycomb repressive complex 2, as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibition of Wnt/β-catenin/TCF function in Ccn6-KO mBrCA cells led to reduced EZH2 levels and decreased histone H3 lysine 27 trimethylation, resulting in deregulation of specific gene targets. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors and induced an epithelial phenotype in vivo. In human breast cancer specimens, low CCN6 is significantly associated with activated β-catenin and high EZH2 in spindle mBrCAs compared to other subtypes. Collectively, our findings establish a novel tumor suppressor mechanism for CCN6 as a key negative regulator of a b-catenin/TCF-EZH2 axis and highlight how CCN6 restoration or b-catenin or EZH2 inhibition could have therapeutic relevance for patients with spindle mBrCAs.
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| Overall design |
This project is to determine by Chip-seq using 3H3K27me3 antibody in 2 CCN6KO Tumor breast cancer cells, parental and transduced with DNTCF4 (a dominant negative Beta catenin construct), how EZH2 can modulate the epigenetics of mice metaplastic breast tumors
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| Contributor(s) |
Gonzalez ME, Calvacante R, Kleer CG, Carruthers N |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Dec 19, 2023 |
| Last update date |
Jul 11, 2024 |
| Contact name |
Bioinformatics Core |
| E-mail(s) |
bioinformatics@umich.edu
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| Organization name |
University of Michigan
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| Street address |
BRCF Bioinformatics Core, 2800 Plymouth Rd
|
| City |
Ann Arbor |
| State/province |
Mi |
| ZIP/Postal code |
48109-2800 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE250575 |
CCN6/WISP3 suppresses metaplastic breast carcinoma by antagonizing a WNT/b-catenin/EZH2 cascade |
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| Relations |
| BioProject |
PRJNA1054561 |
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