Abstract IA017: An oncogenic histone reader promotes metaplastic TNBC

Abstract Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) led to spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2, comprising 70% of all mammary tumors that developed with 40% penetrance. We saw strong correlation of Trim24COE carcinosarcoma tumors with human MpBC tumors and derived a conserved Trim24COE gene signature of Glycolysis, EMT and mTORC1 signaling pathways. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. To assess TRIM24-dependent metabolic alterations, we developed Trim24COE carcinosarcoma spheroid cultures. Tumor-derived Trim24COE carcinosarcoma spheroids exhibit TRIM24-dependent EMT and repressed cellular and mitochondrial ROS levels. We found that TRIM24 expression increased c-myc, NADPH and NRF2 levels to drive ROS repression and TRIM24-dependent cell survival under oxidative stress. TRIM24 mediates NRF2 activation at the level of chromatin structure activation, as shown by ATAC-seq of Trim24COE and shTrim24 carcinosarcoma spheroids. These in vivo and ex vivo models of metaplastic TNBC offer a platform for mechanistic discovery and nomination of potential therapeutic avenues for this highly malignant TNBC subtype. Citation Format: Vrutant V. Shah, Shucheng Miao, Patrick M. Krause, Sabrina A. Stratton, Lalit R. Patel, Michelle C. Barton. An oncogenic histone reader promotes metaplastic TNBC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA017.