A Small-Molecule Inhibitor of TopBP1 Exerts Anti-myc Activity and Synergy With PARP Inhibitors

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A. This leads to the activation of E2F1-mediated apoptosis and the inhibition of mutant p53 gain of function. In addition, 5D4 disrupts the interaction of TopBP1 with MIZ1, which in turn allows MIZ1 to bind to its target gene promoters and repress MYC activity. Moreover, 5D4 inhibits the association of the TopBP1-PLK1 complex and prevents the formation of Rad51 foci. When combined with inhibitors of PARP1/2 or PARP14, 5D4 synergizes to effectively block cancer cell proliferation. Our animal studies have demonstrated the antitumor activity of 5D4 in breast and ovarian cancer xenograft models. Moreover, the effectiveness of 5D4 is further enhanced when combined with a PARP1/2 inhibitor talazoparib. Taken together, our findings strongly support the potential use of TopBP1-BRCT7/8 inhibitors as a targeted cancer therapy

Nuclear Receptors in Breast Cancer

Breast cancer (BC) is classified into four major molecular subtypes. The most predominant subtypes, luminal A and B are hormone receptor-positive BC (ERα +/PR+) which accounts for over 70% of BC cases. ERα +/PR+ breast cancers are treated with selective estrogen-receptor modulators such as tamoxifen, directed against the main therapeutic target estrogen receptor α (ERα). Tumors with HER2+ amplification are targeted by monoclonal antibody trastuzumab which significantly contributes to better prognosis. Finally, Triple-negative breast cancer has no therapeutic target identified, leaving patients with chemotherapy as their main option. Despite the overall success of chemotherapy, endocrine therapy, and the use of monoclonal antibody, one of the major challenges of BC is cancer recurrence. ERα is a member of the super family of nuclear receptors (NRs), which are ligand-dependent transcription factors that are involved in many biological processes associated with cancer. Based on ERα biological importance and utility in the management of BC, we hypothesized that NRs other than ERα might serve as potential markers and offer new therapeutic approaches for BC patients.Biology and Biochemistry, Department o