Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates potential therapeutic targets

Global profiling of tumor expression revealed increased RING-PHD-Bromodomain protein TRIM24 levels in numerous human cancers. Conditional over-expression of Trim24 was sufficient to drive murine mammary tumor development, 70% of which were ER, PR and HER2-negative carcinosarcomas with coexisting malignant epithelial and mesenchymal compartments, offering a unique model of human triple-negative, metaplastic breast cancer (MpBC). Both in vivo and in cellulo, TRIM24 induced EMT, repressing CDH1 and activating EMT factors. Whole exome sequencing of human MpBC tumors and Trim24-driven carcinosarcomas defined a TRIM24-like subclass of MpBC patients with worse overall and relapse-free survival. Among 40 MpBC patients, 43% had robust expression of TRIM24. These studies implicate TRIM24 as a potential biomarker and therapeutic target for a subset of MpBC. To determine the transcriptional changes in mammary specific CRE driven TRIM24 overexpressing tumor versus control Cre expressing mammary glands, we performed RNA sequencing. There are 4 control samples which are mammary glands of Cre exprssing FVB/129 mice. The tumors are obtained from TRIM24 COE mice in a similar background.