PT  - JOURNAL ARTICLE
AU  - Przanowski, Piotr
AU  - Lou, Song
AU  - Tihagam, Rachisan Djiake
AU  - Mondal, Tanmoy
AU  - Conlan, Caroline
AU  - Shivange, Gururaj
AU  - Saltani, Ilyas
AU  - Singh, Chandrajeet
AU  - Xing, Kun
AU  - Morris, Benjamin B.
AU  - Mayo, Marty W.
AU  - Teixeira, Luis
AU  - Lehmann-Che, Jacqueline
AU  - Tushir-Singh, Jogender
AU  - Bhatnagar, Sanchita
TI  - Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer
AID  - 10.1158/0008-5472.CAN-20-1459
DP  - 2020 Nov 01
TA  - Cancer Research
PG  - 4791--4804
VI  - 80
IP  - 21
4099  - http://cancerres.aacrjournals.org/content/80/21/4791.short
4100  - http://cancerres.aacrjournals.org/content/80/21/4791.full
SO  - Cancer Res2020 Nov 01; 80
AB  - 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.