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 Manu; Lei 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

doi:10.1038/s41467-021-25650-z

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

Nat Commun. 2021 Sep 10;12(1):5389. doi: 10.1038/s41467-021-25650-z.

Authors

Vrutant V Shah^#^{1

2}, Aundrietta D Duncan^#^{2

3

4

5}, Shiming Jiang^#^{2

6}, Sabrina A Stratton^{2

3}, Kendra L Allton^{2

7}, Clinton Yam^{2

8}, Abhinav Jain^{2

3

4}, Patrick M Krause^{1

2}, Yue Lu^{2

3}, Shirong Cai^{2

9}, Yizheng Tu^{2

9}, Xinhui Zhou^{2

9}, Xiaomei Zhang^{2

9}, Yan Jiang^{2

9}, Christopher L Carroll^{2

10}, Zhijun Kang^{2

10}, Bin Liu^{2

3}, Jianjun Shen^{2

3}, Mihai Gagea^{2

11}, Sebastian M Manu^{2

3}, Lei Huo^{2

12}, Michael Gilcrease^{2

12}, Reid T Powell¹³, Lei Guo¹³, Clifford Stephan¹³, Peter J Davies¹³, Jan Parker-Thornburg^{1

2}, Guillermina Lozano^{1

2

4}, Richard R Behringer^{1

2

4}, Helen Piwnica-Worms^{2

4

9}, Jeffrey T Chang^{14

15}, Stacy L Moulder^{16

17}, Michelle Craig Barton^{18

19

20

21}

Affiliations

¹ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, TX, USA.
⁵ Salarius Pharmaceuticals, Houston, TX, USA.
⁶ Thoracic Head and Neck Medicine Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ The Neurodegeneration Consortium, Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Institute of Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹² Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M College of Medicine, Houston, TX, USA.
¹⁴ University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, TX, USA. jeffrey.t.chang@uth.tmc.edu.
¹⁵ Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center at Houston, Houston, TX, USA. jeffrey.t.chang@uth.tmc.edu.
¹⁶ The University of Texas MD Anderson Cancer Center, Houston, TX, USA. smoulder@mdanderson.org.
¹⁷ Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. smoulder@mdanderson.org.
¹⁸ The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bartonsh@ohsu.edu.
¹⁹ Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bartonsh@ohsu.edu.
²⁰ University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, TX, USA. bartonsh@ohsu.edu.
²¹ Division of Oncological Sciences, Cancer Early Detection Advanced Research, Center Knight Cancer Institute Oregon Health & Science University, Portland, OR, USA. bartonsh@ohsu.edu.

^# Contributed equally.

Abstract

Conditional overexpression of histone reader Tripartite motif 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast / pathology
Carcinosarcoma / genetics*
Carcinosarcoma / pathology
Carrier Proteins / genetics*
Carrier Proteins / metabolism
Clinical Trials as Topic
Female
Gene Expression Regulation, Neoplastic
Humans
Mammary Glands, Animal / pathology
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Transgenic
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Primary Cell Culture
Proto-Oncogene Proteins c-met / genetics
RNA-Seq
Single-Cell Analysis
Transcription Factors / genetics*
Transcription Factors / metabolism
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / pathology
Whole Genome Sequencing
Xenograft Model Antitumor Assays

Substances

Carrier Proteins
Nuclear Proteins
TRIM24 protein, human
Transcription Factors
transcriptional intermediary factor 1
HGFR protein, mouse
MET protein, human
Proto-Oncogene Proteins c-met

Associated data

figshare/10.6084/m9.figshare.14818542.v1
figshare/10.6084/m9.figshare.14818560.v1
figshare/10.6084/m9.figshare.14818536.v1
figshare/10.6084/m9.figshare.14818575.v1

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding