TRIM21 mediates the synergistic effect of Olaparib and Sorafenib by degrading BRCA1 through ubiquitination in TNBC

Abstract

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive breast cancer with a poor prognosis and a high recurrence rate. Although Olaparib, a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, was approved for germline BRCA-mutated metastatic breast cancer, chemotherapy remains the mainstay of treatment for cancer patients without BRCA mutation. Tripartite motif containing-21 (TRIM21) is one of the TRIM family members that has been implicated in various types of cancer. This study aimed to investigate the prognostic function of TRIM21. It was found that a low TRIM21 expression level was correlated with a poorer overall survival of TNBC patients. TRIM21 depletion promoted the proliferation of TNBC cells in vivo and in vitro, as well as migratory and invasive capabilities in vitro. Importantly, breast cancer susceptibility gene 1 (BRCA1) was identified as a ubiquitination substrate of TRIM21. It was confirmed that BRCA1 was upregulated after Olaparib treatment, which could explain the relative resistance of TNBC cells without BRCA1 mutation to Olaparib. Moreover, Sorafenib, a standard treatment for hepatocellular carcinoma, increased the sensitivity of TNBC cells to Olaparib through TRIM21-mediated ubiquitination degradation of BRCA1. Thus, a synergic effect of Olaparib and Sorafenib was found in vitroand in vivo. The combined treatment also aggravated DNA damage, cell cycle arrest, and apoptosis of TNBC cells. In summary, the findings verified the synergistic effect of Olaparib and Sorafenib and revealed TRIM21 as a potential target for TNBC therapy.