Inactivation of KMT2C in a mouse model of Erbb2/Neu overexpression leads to EMT, mitochondrial dysfunction and improved therapeutic response to lapatinib

Large scale next-generation sequencing of human tumours has uncovered apreviously unappreciated role for epigenetic regulators intumorigenesis. In most solid malignancies including breast cancer,histone modifying enzymes are frequently mutated, while a large portionof mutations are presumed to be loss-of-function, implying that thoseenzymes act as tumour suppressors. Histone 3 lysine 4 methyltransferaseKMT2C/MLL3, which has been implicated in oestrogen receptor-driventranscription, is mutated in >10% of breast tumours. To study theputative tumour suppressor role of KMT2C in breast cancer, we havegenerated mouse models of Erbb2/Neu, Myc or PIK3CA-driven tumorigenesis,in which the KMT2C locus is knocked out specifically in the luminallineage of mouse mammary glands by means of Cre recombinase. While KMT2Cinactivation alone has no significant effect in mammary homeostasis,mice lacking KMT2C activity develop tumours with shorter latency,irrespectively of the driving oncogene, assigning a bona fide tumoursuppressor role for KMT2C in mammary tumorigenesis. Moreover, loss ofKMT2C activity leads to extensive epigenetic and transcriptional changesleading to increased ERK1/2 activity, extracellular matrixre-organization and epithelial-to-mesenchymal transition, as well asmitochondria dysfunction which leads to increased reactive oxygenspecies production. In Erbb2/Neu-driven tumours, loss of KMT2C leads toincreased oncogene addiction and hyper-dependence on Erbb2/Neu activity,rendering these tumours highly responsive to lapatinib treatment.Collectively, our findings solidify the role of KMT2C as a tumoursuppressor in breast cancer and identify dependencies that could betherapeutically relevant.