Oncogenic TRIM37-driven chemo-resistance in triple negative breast cancer

Triple negative breast cancer (TNBC) accounts for nearly 40,000 deaths annually in the United States alone and predominantly affects younger African American women. Despite an initial positive response to chemotherapy, TNBC has the highest risk of relapse, highest frequency of metastasis, and worst overall survival rate of any breast cancer. This poor prognosis is in part due to unidentified molecular mechanisms of chemo-resistance as well as no preferred standard therapy for patients due to a lack of actionable therapeutic targets for TNBC. We have discovered a new metastasis promoting function for oncogenic tripartite motif-containing 37 (TRIM37), an E3 ubiquitin ligase that Bhatnagar lab has previously identified and characterized. To this end, we have shown that depletion of TRIM37, using short hairpin RNA, renders TNBC cells sensitive to chemotherapeutic agents, such as doxorubicin, etoposide, and cisplatin. Surprisingly, we have also found chemotherapy-induced amplification of oncogenic TRIM37 in TNBC cells. Most importantly, we have found that when highly immunodeficient NOD scid gamma mice are given subcutaneous TRIM37-depleted TNBC tumors, these tumors are more sensitive to doxorubicin when compared to control TNBC tumors. Collectively, our findings not only support our hypothesis that TRIM37 plays a role in TNBC chemo-resistance both in vitro and in vivo, but also indicate TRIM37 as an oncogenic target in an innovative therapeutic approach for treating TNBC with the potential to selectively eliminate TNBC chemo-resistant cells.