The role of USP7 in TNBC proteomes

ABSTRACT: The deubiquitinase USP7 plays an important role in tumorigenesis and is a key regulator of the MDM-p53 pathway. Emerging evidence also supports USP7’s p53-independent roles in proliferation and tumorigenesis. Triple negative breast cancers recurrently inactivate p53 and this disease subtype remains difficult to treat and in need of new therapeutic options. We show here that USP7 is upregulated at the protein level in TNBC patient tumors. Importantly, genetic and pharmacologic USP7 inactivation impaired tumor progression in TNBC animal models. To gain insight into the role of USP7 in p53-mutant TNBCs, we performed deep quantitative proteomics in multiple TNBC cell lines. This revealed an overlapping set of USP7 targets which collectively contribute to cell proliferation and survival. Acute USP7 inactivation allowed us to infer proximally controlled proteins which are likely direct targets. Surprisingly, many of the proteins downregulated by USP7 inhibition are E3 ubiquitin ligases. Thus, a key function of USP7 antagonizes the degradation of enzymes that perform ubiquitination, since these enzymes are often susceptible to auto-ubiquitination and degradation. We validate several new substrates, including the dual ubiquitin- and SUMO-ligase TOPORS, which is implicated in DNA damaging signaling. We find that TOPORS interacts with the BRCA1-A DNA damage repair complex suggesting a USP7-TOPORS-BRAC1-A axis that might further explain the continued proliferation of genomically unstable TNBCs. Collectively, these data nominate USP7 as a potential therapeutic in TNBC through its role in maintaining proteostasis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Angie Mordant  

LAB HEAD: Michael Emanuele

PROVIDER: PXD059910 | Pride | 2026-05-21

REPOSITORIES: Pride