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

Vrutant Shah ,Kendra L Allton,Xiaomei Zhang,Christopher L Carroll,Peter J Davies,Yan Jiang,Xinhui Zhou,Shirong Cai,Reid T Powell,Jeffrey T Chang,Patrick M Krause,Guillermina Lozano,Yizheng Tu,Jianjun Shen,Helen Piwnica‐Worms ,Jan Parker-Thornburg,Shiming Jiang,Clifford Stephan,Bin Liu,Mihai Gagea,Zhijun Kang,Michael Z Gilcrease ,Aundrietta D Duncan,Richard R Behringer,Lei Guo,Abhinav K Jain ,Stacy L Moulder,Lei Huo,Yao Lu ,Sebastian M Manu,Sabrina A Stratton,Clinton Yam,Michelle C Barton

doi:10.1038/s41467-021-25650-z

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.

Highlights

4,13,17 ✉, 1234567890():,; Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking estrogen receptor (ER), progesterone receptor (PR) and HER2
We show that TRIM24-mediated, epigenetic activation of c-Met is disrupted by selective inhibitors, Crizotinib and PHA665752, in a dose-dependent manner in primary metaplastic carcinosarcoma tumor cells. c-Met induces up-regulation of PI3K and mammalian target of rapamycin (mTOR) pathways at a protein level, consistent with our Reverse Phase Protein Array (RPPA) and cytometry by timeof-flight (CyTOF) analysis of TRIM24COE metaplastic carcinosarcomas
Using a dual inhibitor developed for human PI3K isoforms and mTOR, we showed that viability of murine TRIM24COE metaplastic carcinosarcoma cells was likewise inhibited, further supporting the parallels between human cancers and tumors arising in the TRIM24COE mouse model

Summary

Introduction

4,13,17 ✉, 1234567890():,; 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. 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. Advances in next-generation sequencing (NGS) and mapping of genome-wide epigenetic marks show that epigenetic regulators are frequently mutated and/or aberrantly expressed in numerous diseases, including cancers, often in correlation with poor survival or therapeutic resistance[1]. Among these epigenetic regulators are proteins with structural domains that “read” epigenetic modifications and selectively interact with specific histone or non-histone post-translational modifications (PTMs). Molecular characterization by next-generation sequencing (NGS) of MpBC patient tumors and patient-derived xenografts (PDXs) of MpBC revealed some potential targets; there is limited ability to define a molecular landscape with a large patient cohort in this rare

Methods

Results

Conclusion