Understanding the Function of EZH2 as a Determinant of Breast Cancer Invasion and Metastasis.

摘要

EZH2 exerts oncogenic functions in breast cancer, where its overexpression is associated with metastasis. While it reportedly acts a transcriptional repressor, EZH2 may exhibit context-dependent activating functions. Despite associations with worse outcome and metastasis in breast cancer, a functional role for EZH2 in breast cancer metastasis in vivo has not been demonstrated. Also, whether EZH2 regulates cancer cell phenotype and motility are unknown. We discovered that EZH2 knockdown induces a phenotypic reprogramming from mesenchymal to epithelial, and reduces motility and invasion in breast cancer cells. In vivo, EZH2 knockdown decreased spontaneous metastasis to the lungs in mice. We found a role for EZH2 in inducing the p38 signaling pathway, an important regulator of breast cancer invasion and metastasis. In breast cancer cells, EZH2 bound to phosphorylated p38 (p-p38) in association with other core members of the Polycomb Repressive Complex 2, and EZH2 overexpression led to increased levels of p-p38 and of activated, downstream pathway proteins. The effect on pp38 was confirmed in vivo as it correlated with decreased spontaneous metastasis. In clinical specimens of matched primary and invasive breast carcinomas, EZH2 expression was up- regulated in 100% of metastases, and EZH2 and p-p38 were coexpressed in 63% of cases. These findings reveal a new mechanism by which EZH2 functions in breast cancer.