Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2020
- Source ID
- 10.1158/0008-5472.can-20-1459
Entities
People
- Benjamin B Morris
- Caroline Conlan
- Chandrajeet Singh
- Gururaj Shivange
- Ilyas Saltani
- Jacqueline Lehmann-che
- Jogender Tushir-singh
- Kun Xing
- Luis Teixeira
- Marty W Mayo
- Piotr Przanowski
- Rachisan Djiake Tihagam
- Sanchita Bhatnagar
- Song Lou
- Tanmoy Mondal
Organizations
- Assistance Publique – Hôpitaux de Paris
- National Institutes of Health
- United States Department of Defense
- University of Virginia