Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer

Vrutant V. Shah, Aundrietta D. Duncan, Shiming Jiang, Sabrina A. Stratton, Kendra L. Allton, Clinton Yam, Abhinav 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. ManuLei Huo, Michael 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 Craig Barton

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5389
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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