Canonical and non-canonical roles of the histone methyltransferase EZH2 in mammary development and cancer.

Although hormones and downstream transcription factors are considered main drivers directing mammary gland development and oncogenic transformation, an emerging body of evidence suggests these processes are modulated by dynamic histone methylation landscapes. The methyltransferase EZH2 catalyzes the formation of trimethyl groups on lysine 27 of histone 3 (H3K27me3) and loss- and gain-of-function studies have provided insight into its role in normal mammary development and oncogenic transformation. EZH2 controls the homeostasis of mouse mammary stem cells, and mammary epithelium devoid of EZH2 does not undergo functional development during pregnancy, possibly due to a paucity of stem cells. EZH2 levels are frequently elevated in breast cancer suggesting a link between H3K27me3 and cell proliferation. In addition to its role as epigenetic regulator, recent studies have placed EZH2 into the category of transcriptional co-activators and thus opened the possibility of non-canonical signaling pathways. In contrast to solid tumors, loss of EZH2 from hematopoietic cells has been linked to malignancies (Fig. 1). The challenge will be to understand not only cell-specific functions of EZH2, but also the extent to which it relies on its enzymatic activity versus its ability to serve as a transcriptional co-factor.