Mutations in MLL3 promote breast cancer progression via HIF1α-dependent intratumoral recruitment and differentiation of regulatory T cells.

ABSTRACT: Loss-of-function mutations in MLL3, encoding the histone methyltransferase MLL3/KMT2C, are frequent in various cancer types. To examine the mechanisms whereby MLL3 suppresses tumorigenesis, we developed a mouse mammary-stem-cell-based tumor model bearing cancer-driver mutations, including loss of MLL3/KMT2C and p53 and constitutive phosphatidylinositol 3-kinase (PI3K) activation, recapitulating a genetic makeup of aggressive human breast cancers. MLL3 loss stabilized the transcription factor HIF1α, which increased secretion of the chemokine CCL2 by tumor cells and promoted recruitment of CCR2⁺ regulatory T (Treg) cells. Treg cell depletion slowed tumor onset and progression. In human breast tumors, infiltration of Treg cells correlated with the presence of MLL3 mutations. HIF1α

SUBMITTER: Boutet M 

PROVIDER: S-EPMC12344594 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature