Abstract B064: KDM2-mediated epigenetic mechanism regulates brain metastasis of breast cancer

Abstract Metastatic brain tumors are frequently observed in breast cancer patients, particularly those with the HER2+ and triple-negative breast cancer (TNBC) subtypes, and are associated with the shortest disease-specific survival. Despite this clinical observation, specific therapies for brain metastases remain unavailable due to the lack of actionable molecular targets. Here, we focused on the high cellular stress feature in the brain microenvironment and identified a low level of H3K36me2 and high expression of KDM2A H3K36me2 demethylase as key features that contribute to the metastatic fitness of breast cancer cells in the brain. Multiplexed spatial protein analysis on clinical TNBC brain metastasis tissues using the CODEX platform revealed that the low level of H3K36me2 in TNBC cells was associated with a proliferative phenotype and a unique metastatic brain tumor microenvironment. Knockout of KDM2A and its paralog KDM2B preferentially inhibited cellular growth in the cellular stress condition and suppressed brain metastasis outgrowth in a preclinical model. Mechanistically, we identified that KDM2 plays a crucial role in maintaining transcriptional fitness under cellular stress, potentially providing the metastatic fitness advantage in the brain microenvironment. In summary, targeting epigenetic systems presents a promising strategy to control the progression of breast cancer brain metastases. Citation Format: Jun Nishida, Zheqi Li, Marco Seehawer, Kun Huang, Oscar Lin, Shreya Nakhawa, Maxime Meylan, Ye Tian, Graham L. Barlow, Elinor G. Sterner, Xinran Cai, Kimberly A. Parker, Marie-Anne Goyette, Pierre Foidart, Laura Stevens, Ashka Patel, Deborah Dillon, Kai Wucherpfennig, Nancy U. Lin, Matthew G. Vander Heiden, Kornelia Polyak. KDM2-mediated epigenetic mechanism regulates brain metastasis of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B064.