1. Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
- Author
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Lei Huo, Abhinav K. Jain, Christopher Carroll, Jan Parker-Thornburg, Guillermina Lozano, Shirong Cai, Sabrina A. Stratton, Mihai Gagea, Michelle Craig Barton, Yan Jiang, Clifford Stephan, Michael Z. Gilcrease, Xinhui Zhou, Patrick M. Krause, Vrutant Shah, Lei Guo, Xiaomei Zhang, Stacy L. Moulder, Shiming Jiang, Peter J.A. Davies, Aundrietta D. Duncan, Helen Piwnica-Worms, Jianjun Shen, Clinton Yam, Richard R. Behringer, Zhijun Kang, Reid T. Powell, Bin Liu, Kendra Allton, Yue Lu, Yizheng Tu, Sebastian M. Manu, and Jeffrey T. Chang
- Subjects
Science ,Primary Cell Culture ,General Physics and Astronomy ,Mice, Transgenic ,Triple Negative Breast Neoplasms ,General Biochemistry, Genetics and Molecular Biology ,TRIM24 ,Mice ,Mammary Glands, Animal ,Breast cancer ,Carcinosarcoma ,medicine ,Animals ,Humans ,Breast ,RNA-Seq ,Epigenetics ,skin and connective tissue diseases ,PI3K/AKT/mTOR pathway ,Regulation of gene expression ,Clinical Trials as Topic ,Multidisciplinary ,Whole Genome Sequencing ,biology ,Mammary Neoplasms, Experimental ,Nuclear Proteins ,General Chemistry ,Proto-Oncogene Proteins c-met ,Gene signature ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Histone ,biology.protein ,Cancer research ,Female ,Single-Cell Analysis ,Carrier Proteins ,Transcription Factors - Abstract
Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) 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 Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE 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 Trim24COE 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.
- Published
- 2021