Loss of Kmt2c in vivo leads to EMT, mitochondrial dysfunction and improved response to lapatinib in breast cancer

Abstract

Deep sequencing of human tumours has uncovered a previously unappreciated role for epigenetic regulators in tumorigenesis. H3K4 methyltransferase KMT2C/MLL3 is mutated in several solid malignancies, including more than 10% of breast tumours. To study the tumour suppressor role of KMT2C in breast cancer, we generated mouse models of Erbb2/Neu, Myc or PIK3CA-driven tumorigenesis, in which the Kmt2c locus is knocked out specifically in the luminal lineage of mouse mammary glands using the Cre recombinase. Kmt2c knock out mice develop tumours earlier, irrespective of the oncogene, assigning a bona fide tumour suppressor role for KMT2C in mammary tumorigenesis. Loss of Kmt2c induces extensive epigenetic and transcriptional changes, which lead to increased ERK1/2 activity, extracellular matrix re-organization, epithelial-to-mesenchymal transition and mitochondrial dysfunction, the latter associated with increased reactive oxygen species production. Loss of Kmt2c renders the Erbb2/Neu-driven tumours more responsive to lapatinib. Publicly available clinical datasets revealed an association of low Kmt2c gene expression and better long-term outcome. Collectively, our findings solidify the role of KMT2C as a tumour suppressor in breast cancer and identify dependencies that could be therapeutically amenable.

Genomic characterization reveals distinct mutational landscapes and therapeutic implications between different molecular subtypes of triple-negative breast cancer

“…Mutations in the epigenetic regulator MLL3 were observed to be key drivers of the hybrid epithelial/mesenchymal phenotype and metastasis in breast cancer 31 . Loss of MLL3 in vivo improved response to lapatinib in breast cancer 32 . It is suggested that MLL3 could be a potential therapeutic target for patients i n IM subtype.…”

Constructing a prognostic model based on MPT-related genes and investigate the characteristics of immune infiltration in bladder cancer

“…Epigenetic modi cations, such as DNA methylation and histone acetylation, can affect the expression level of KMT2C gene. Some studies have found that loss of KMT2C in breast cancer can lead to EMT and mitochondrial dysfunction [42], but no relevant reports have been found in bladder cancer. Our results showed an increase in multi-hit mutations, a decrease in missense mutations, and a decrease in overall mutations in the high-risk group, which is contrary to the results in breast cancer, which may be related to different cancer types or sample error.…”

KMT2 (MLL) family of methyltransferases in head and neck squamous cell carcinoma: A systematic review

“…Consistently, another study utilizing animal model to investigate prostate cancer showed that samples with mutated Kmt2c displayed a Myc gene signature and loss of p16 INK4A , 99 facilitating tumor growth and metastasis. Additionally, Kmt2c loss in a breast cancer mice model led to Epithelial‐to‐Mesenchymal Transition (EMT), extracellular matrix re‐organization, activation of ERK1/2, and mitochondrial dysfunction with ROS accumulation 100 . Therefore, the loss of KMT2C function may be an important oncogenic event that interferes with tumor suppressor mechanisms.…”

“…Additionally, Kmt2c loss in a breast cancer mice model led to Epithelialto-Mesenchymal Transition (EMT), extracellular matrix re-organization, activation of ERK1/2, and mitochondrial dysfunction with ROS accumulation. 100 Therefore, the loss of KMT2C function may be an important oncogenic event that interferes with tumor suppressor mechanisms.…”