Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets. We have obtained gene expression profiles of 8 treatment-naïve metaplastic tumors and 20 treatment-naïve non-metaplastic tumors from triple-negative breast cancer patients. -------------------------------------------------------- ***Submitter states the following: Due to IRB restrictions, we are required to use a controlled-access database for the raw data. Thus, we cannot upload the raw data to SRA. We are currently in the process of uploading it to EGA. --------------------------------------------------------