TY - JOUR
T1 - Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
AU - Shah, Vrutant V.
AU - Duncan, Aundrietta D.
AU - Jiang, Shiming
AU - Stratton, Sabrina A.
AU - Allton, Kendra L.
AU - Yam, Clinton
AU - Jain, Abhinav
AU - Krause, Patrick M.
AU - Lu, Yue
AU - Cai, Shirong
AU - Tu, Yizheng
AU - Zhou, Xinhui
AU - Zhang, Xiaomei
AU - Jiang, Yan
AU - Carroll, Christopher L.
AU - Kang, Zhijun
AU - Liu, Bin
AU - Shen, Jianjun
AU - Gagea, Mihai
AU - Manu, Sebastian M.
AU - Huo, Lei
AU - Gilcrease, Michael
AU - Powell, Reid T.
AU - Guo, Lei
AU - Stephan, Clifford
AU - Davies, Peter J.
AU - Parker-Thornburg, Jan
AU - Lozano, Guillermina
AU - Behringer, Richard R.
AU - Piwnica-Worms, Helen
AU - Chang, Jeffrey T.
AU - Moulder, Stacy L.
AU - Barton, Michelle Craig
N1 - Funding Information:
We thank L. R. Patel and the Lozano lab for their help and valuable input, as well as L. Gechijian, N. Gray and J. Bradner for their kind gift of a TRIM24 PROTAC. This study was supported by National Institutes of Health grant RO1 CA214871 to MCB and GL, the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots ProgramTM, and the MD Anderson Cancer Center National Cancer Institute Cancer Center Support Grant (CCSG) CA016672. We are grateful to the patients who provided tumor biopsies for PDX model establishment. PDX models and derivatives were obtained from the Cazalot Breast Cancer Model Resource, established through a gift from the Cazalot family and from funds from the MDACC Breast Cancer Moon Shot Program. Additional funding sources that supported this work include the Cancer Prevention and Research Institute of Texas (CPRIT) grants RP160710 (to H.P-W., J.T.C. and P.J.D.) and RP150578 (to P.J.D). Transgenic animals were created at the MD Anderson Cancer Center Genetically Engineered Mouse Facility with the support of CCSG (P30CA016672) and R50 (R50CA211121) grants. RNA-Sequencing was performed at MD Anderson Cancer Center Science Park Next-Generation Sequencing Facility supported by CPRIT Core Facility Support Grants (RP120348 and RP170002). IHC was performed with the support of CCSG-funded Science Park Research Histology, Pathology and Imaging Core (RHPI) at University of Texas MD Anderson Cancer Center Science Park, the Flow Cytometry and Cell Imaging Core shared resource and Histopathology core of the Department of Veterinary Medicine & Surgery are partially funded by NCI Cancer Center Support Grant P30CA16672. High-throughput drug screening was performed at the Texas A&M Combinatorial Drug Discovery Program (CPRIT CFSA RP150578).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25650-z
DO - 10.1038/s41467-021-25650-z
M3 - Article
C2 - 34508101
AN - SCOPUS:85114859333
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5389
ER -