The deubiquitinating enzyme STAMBP is a newly discovered driver of triple-negative breast cancer progression that maintains RAI14 protein stability

Triple-negative breast cancer (TNBC) is a heterogeneous malignancy in women. It is associated with poor prognosis, aggressive malignant behavior, and limited treatment options. In the ubiquitin‒proteasome system (UPS), deubiquitinases (DUBs) are potential therapeutic targets for various tumors. In this study, by performing unbiased siRNA screening, we identified STAMBP, a JAMM metalloprotease in the DUB family, as a driver of human TNBC tumor growth. Functionally, the knockdown of STAMBP inhibited the proliferation, migration, and invasion of multiple TNBC cell lines. Immunoprecipitation–mass spectrometry combined with functional and morphological analysis verified the interaction between STAMBP and the actin-binding protein RAI14. Mechanistically, STAMBP stabilized the RAI14 protein by suppressing the K48-linked ubiquitination of RAI14 and thus prevented its proteasomal degradation. Therefore, knocking down STAMBP resulted in the reduction in RAI14 protein levels and suppression of tumor growth in vitro and in vivo. Importantly, high levels of STAMBP were correlated with poor prognosis in TNBC patients. In summary, we reveal a previously unrecognized DUB pathway that promotes TNBC progression and provides a rationale for potential therapeutic interventions for the treatment of TNBC. Breast cancer: Novel therapeutic target identified for triple-negative subtype An enzyme that promotes tumor growth in triple-negative breast cancer (TNBC), one of the five main breast cancer subtypes, could provide a novel treatment target for this aggressive, life-limiting disease. There are limited treatment options for TNBC, and tumors often develop resistance to chemotherapy. Now, Xin Chen and Jinbao Liu at the Guangzhou Medical University, China, and co-workers have identified a key deubiquitinating enzyme involved in tumor growth in TNBC. High levels of this enzyme, the STAM binding protein (STAMBP), are associated with poor prognosis in patients. In experiments on human cell cultures and a mouse model, the team found that STAMBP stabilizes a particular protein, RAI14, that facilitates the growth of TNBC cells. Knocking out STAMBP reduced levels of this protein, consequently inhibiting cell proliferation, migration, and invasion.