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Tumor Biology and Immunology

Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer

Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B. Morris, Marty W. Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh and Sanchita Bhatnagar
Piotr Przanowski
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Song Lou
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Rachisan Djiake Tihagam
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Tanmoy Mondal
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Caroline Conlan
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Gururaj Shivange
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Ilyas Saltani
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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  • ORCID record for Ilyas Saltani
Chandrajeet Singh
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Kun Xing
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Benjamin B. Morris
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
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Marty W. Mayo
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
2UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia.
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Luis Teixeira
3Breast Disease Unit, AP-HP, Hospital Saint Louis, Paris, France.
4University of Paris, INSERM U976, HIPI, IRSL-Saint Louis, Paris, France.
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Jacqueline Lehmann-Che
4University of Paris, INSERM U976, HIPI, IRSL-Saint Louis, Paris, France.
5Molecular Oncology Unit, AP-HP Hospital Saint Louis, Paris, France.
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Jogender Tushir-Singh
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
2UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia.
6Laboratory of Novel Biologics, University of Virginia School of Medicine, Charlottesville, Virginia.
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  • For correspondence: sb5fk@virginia.edu jogi@virginia.edu
Sanchita Bhatnagar
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
2UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia.
7Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia.
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  • For correspondence: sb5fk@virginia.edu jogi@virginia.edu
DOI: 10.1158/0008-5472.CAN-20-1459 Published November 2020
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Abstract

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1–conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention.

Significance: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • S. Bhatnagar and J. Tushir-Singh are lead contacts of this article.

  • Cancer Res 2020;80:4791–804

  • Received May 1, 2020.
  • Revision received July 21, 2020.
  • Accepted August 19, 2020.
  • Published first August 27, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (21)
November 2020
Volume 80, Issue 21
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Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer
Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B. Morris, Marty W. Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh and Sanchita Bhatnagar
Cancer Res November 1 2020 (80) (21) 4791-4804; DOI: 10.1158/0008-5472.CAN-20-1459

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Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer
Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B. Morris, Marty W. Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh and Sanchita Bhatnagar
Cancer Res November 1 2020 (80) (21) 4791-4804; DOI: 10.1158/0008-5472.CAN-20-1459
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