Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
Vrutant Shah, Aundrietta D. Duncan, Shiming Jiang, Sabrina A. Stratton, Kendra Allton, Clinton Yam, Abhinav K. Jain, Patrick M. Krause, Yue Lu, Shirong Cai, Yizheng Tu, Xinhui Zhou, Xiaomei Zhang, Yan Jiang, Christopher L. Carroll, Zhijun Kang, Bin Liu, Jianjun Shen, Mihai Gagea, Sebastian M. Manu, Lei Huo, Michael Z. Gilcrease, Reid T. Powell, Lei Guo, Clifford Stephan, Peter J. Davies, Jan Parker‐Thornburg, Guillermina Lozano, Richard R. Behringer, Helen Piwnica‐Worms, Jeffrey T. Chang, Stacy L. Moulder, Michelle Barton
Abstract
Abstract Conditional overexpression of histone reader Tri partite m otif containing protein 24 (TRIM24) in mouse mammary epithelia ( Trim24 COE ) 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 COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24 COE 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 COE 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.