Contrasting roles of KMT2C and KMT2D in breast cancer

KMT2C and KMT2D are paralogous lysine-methyltransferases that primarily monomethylate lysine residues at enhancer regions promoting an active transcriptional state. KMT2C and KMT2D are frequently mutated in multiple cancer types and in breast cancers mutations collectively occur at frequencies of 10-20%. However, the specificity and unique functions of the paralogues in breast cancer development are unclear. Using a combination of mutation, transcriptome, ChIP-seq, chromatin accessibility, and cell proliferation data from breast cancer patient and cell line samples we have investigated the roles of these proteins in tumour development. We identified a dependency of oestrogen receptor (ER) positive breast cancer cell lines on wildtype KMT2D. KMT2D ChIP-seq peaks show greater enrichment and interaction with ER and its binding partners FOXA1 and GATA3 compared to KMT2C in MCF-7 cells and uniquely bind enhancers of a set of genes enriched for oestrogen response pathways. Both KMT2C and KMT2D mutant luminal patient samples show significant downregulation of oestrogen response pathways compared to wildtype which, for KMT2C mutants, correlates with reduced chromatin accessibility around enhancers. Our results suggest that KMT2C and KMT2D have contrasting and subtype-specific roles in breast cancers and reveals KMT2D in particular as a potential target in ER + subtypes.