IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Pygopus2 interaction with H3K4me3 is important for malignant progression of breast cancer
Autor/es:
RUBINSTEIN NATALIA; DAVID BUECHEL; GERHARD CHRISTOFORI; ANDREA VETTIGER; CLAUDIO CANTU; MEERA SAXENA; JONAS FISCHER; KONRAD BASLER
Reunión:
Simposio; ISREC-SCCL Symposium 2016: Horizons of Cancer Biology and Therapy; 2016
Resumen:
Pygopus2 (Pygo2), an obligatory nuclear component of β-catenin-TCF/LEF transcription regulatory complex functions as a co-activator of Wnt/β-catenin signaling. Recently, Pygo2 has been found to be upregulated in breast cancer and its knockout has been shown to decrease mammary tumor growth. By binding to histone H3 trimethylated lysine (H3K4me3), Pygo2 can also participate in chromatin reading and writing. To investigate the relevance of this interaction in malignant progression of breast cancer, we have generated a knockin mouse model wherein Pygo2 cannot bind to H3K4me3 (PyMT-Pygo2A342E/A342E). Compared with the Pygo2 WT mice, the Pygo2A342E/A342E mice formed significantly smaller mammary tumors and lower incidence of lung metastasis. Immunohistochemical analysis revealed that the mutant mice have significantly lesser number of proliferating cells compared with the control mice. Further, the mutant tumors were also enriched in CK8/18 positive luminal cells and demonstrated elevated Notch signaling. Cell lines derived from primary tumors of the mutant mice had a lower proliferation rate and also did not undergo a significant epithelial to mesenchymal transition (EMT) in response to TGFβ treatment. Further, while the WT cell lines activated Wnt signaling in response to Wnt3a stimulation, the mutant cells lines were unable to do so. Collectively, our results suggest that Pygo2 interaction with H3K4me3 is critical for malignant breast tumor progression and it might do so by activating the Wnt/β-catenin signaling that is known to support a basal and aggressive fate of mammary cells. Pygo2-H3K4me3 interaction might therefore serve as an attractive therapeutic target for breast cancer.