人类肿瘤的深度测序揭示了表观遗传调节因子在肿瘤发生过程中之前未被完全认识的作用。H3K4甲基转移酶KMT2C/MLL3在多种实体恶性肿瘤中发生突变，其中包括10%以上的乳腺肿瘤。为了研究KMT2C在乳腺癌中的抑癌作用，我们使用Cre重组酶将Kmt2c基因位点特异性敲除在小鼠乳腺腔上皮细胞系中，生成了Erbb2/Neu、Myc或PIK3CA驱动的肿瘤发生的小鼠模型。Kmt2c敲除小鼠的肿瘤早期发生，不受致癌基因的影响，将KMT2C划分为乳腺肿瘤发生的真正抑癌基因。Kmt2c丧失会引起广泛的表观遗传和转录改变，导致ERK1/2活性增加、细胞外基质重构、上皮-间充质转化和线粒体功能障碍，后者与增加的活性氧自由基产生有关。Kmt2c敲除使Erbb2/Neu驱动的肿瘤对拉帕替尼更具响应性。公开的临床数据集揭示了Kmt2c基因表达下调与更好的长期预后之间的关联。综上所述，我们的研究结果巩固了KMT2C在乳腺癌中的抑癌作用，并发现了可供治疗的依赖性。© 2023. 作者（们）。

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.© 2023. The Author(s).