Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34508101.
- Also identified by DOI 10.1038/s41467-021-25650-z and PMC identifier 8433435.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24<sup>COE</sup>) drives spontaneous development of mammary 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 Trim24<sup>COE</sup> metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24<sup>COE</sup> gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24<sup>COE</sup> tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.
Medical subject headings
- Carcinosarcoma
- Carrier Proteins
- Mammary Neoplasms, Experimental
- Nuclear Proteins
- Transcription Factors
- Triple Negative Breast Neoplasms