Ubiquitin-Specific Proteases in Breast Cancer: Unraveling Oncogenic Roles and Therapeutic Opportunities

The ubiquitin-proteasome system (UPS) is a crucial determinant of protein stability and activity in various aspects of physiological function and disease development. The well-characterized class of regulatory enzymes within the UPS is deubiquitinating enzymes (DUBs), and their effects, particularly those of the ubiquitin-specific proteases (USPs), oppose ubiquitination. All DUB activities can be more or less disrupted in various cancers, including breast cancer, and DUB alterations contribute substantially to tumor initiation, progression, and many forms of therapeutic resistance. In this review, we discuss the various molecular mechanisms of action of USPs on breast cancer hallmarks, including proliferation, aggression or metastasis, evasion of apoptosis, immune evasion, and metabolic programming. We evaluate how specific USPs stabilize oncogene members by deubiquitinating target proteins or deubiquitinating tumor suppressors, thereby influencing a variety of cellular behaviors, from regulating the cell cycle to modulating immune responses. Due to their important role in breast cancer pathology, the alterations of USP activities and the functional roles of selective USPs will also demonstrate some ways USPs present promising therapeutic targets in breast cancer. We will provide a comprehensive overview of USP inhibitors to date, focusing on their utilization in developing and describing efficacy in breast cancer models. Pharmacological inhibitors of specific USPs, such as pimozide, trifluoperazine, rottlerin, 6-thioguanine, and costunolide, are highlighted for their potential to inhibit proliferation, metastasis, induce apoptosis, and circumvent therapy resistance across breast cancer subtypes (triple-negative and HER-2 positive). The review highlights the complex and often contradictory roles of USPs in breast cancer and points to the immense promise of targeting these enzymes to develop new and efficacious anticancer therapies.