USP7 inhibition perturbs proteostasis and tumorigenesis in triple-negative breast cancer

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Abstract The deubiquitinase USP7 is a critical regulator of tumorigenesis, known for stabilizing the MDM2-p53 pathway. Emerging evidence highlights USP7’s p53-independent roles in proliferation and tumorigenesis. Our study reveals that USP7 is broadly upregulated in breast cancer, including triple-negative breast cancer (TNBC), a subtype characterized by near-universal TP53 loss. This provides a model to investigate p53-independent functions of USP7. Using TNBC models, we define p53-independent roles of USP7 in regulating proteostasis and tumorigenesis. Importantly, genetic and pharmacologic USP7 inactivation impaired tumor progression in TNBC models. To explore USP7’s role in p53-mutant TNBCs, we performed deep quantitative proteomics across TNBC cell lines, identifying shared USP7 targets involved in cell proliferation, genome stability, and proteostasis. Acute USP7 inactivation allowed us to infer proximally controlled proteins that are likely direct targets. Surprisingly, many of the proteins downregulated by USP7 inhibition are E3 ubiquitin ligases. Thus, a key USP7 function in TNBC is to antagonize the degradation of ubiquitinating enzymes, since these enzymes are often susceptible to auto-ubiquitination and degradation. Notably, we identified TOPORS, a dual ubiquitin- and SUMO-ligase, among novel USP7 substrates. TOPORS interacts with the BRCA1-A DNA damage repair complex, suggesting a USP7-TOPORS-BRCA1-A axis that might further explain the continued proliferation of genomically unstable TNBCs. Collectively, these data nominate USP7 as a potential therapeutic vulnerability in TNBC.

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