# Targeting lysine methyltransferase 2C deficiency: New frontiers in breast cancer therapy and prognosis

## TL;DR

This paper reviews how KMT2C deficiency contributes to breast cancer progression and explores new treatment strategies for tumors with this mutation.

## Contribution

The paper provides a comprehensive overview of KMT2C's role in breast cancer and highlights novel therapeutic approaches for KMT2C-deficient tumors.

## Key findings

- KMT2C deficiency is linked to tumor heterogeneity, metastasis, and therapy resistance in breast cancer.
- KMT2C interacts with oncogenic pathways like IFNγ-EMT/MET and MAPK/ERK-RAS/PI3K/AKT/mTOR.
- Targeted therapies such as epigenetic modulators and DDR inhibitors show promise for KMT2C-deficient tumors.

## Abstract

Loss‐of‐function mutations in lysine methyltransferase 2 (KMT2C) are frequently observed in breast cancer and are significantly associated with enhanced tumour heterogeneity, aggressive clinical behaviour, and poor prognosis. Although KMT2C has been established as a tumour suppressor, the precise molecular mechanisms by which its deficiency drives metastasis and therapy resistance remain incompletely understood. This review comprehensively examines the multifaceted roles of KMT2C in breast cancer pathogenesis, with a particular emphasis on its interplay with critical oncogenic signalling networks and functional axes, including the IFNγ‐EMT/MET axis, the MAPK/ERK and RAS/PI3K/AKT/mTOR pathways, and the KDM6A–MMP3 regulatory circuit. Furthermore, we discuss emerging therapeutic strategies for KMT2C‐deficient breast cancers, such as epigenetic modulators (EZH2 inhibitors, KDM6A inhibitors, and BET inhibitors), DNA damage response (DDR)‐targeting agents, and pathway‐specific inhibitors. These insights not only elucidate the complex biological functions of KMT2C in breast cancer but also provide a rationale for developing precision therapies tailored to KMT2C‐mutant tumours.

This graphical abstract illustrates the role of KMT2C loss‐of‐function in promoting breast cancer progression and therapeutic vulnerability. KMT2C deficiency drives tumor heterogeneity, metastasis, and therapy resistance by activating oncogenic pathways such as IFNγEMT/MET and MAPK/ERKRAS/PI3K/AKT/mTOR, along with epigenetic remodeling via the KDM6AMMP3 axis. These alterations concurrently create opportunities for targeted treatment using epigenetic drugs, DDR inhibitors, and pathway‐specific therapies.