Copper orchestrates triple-negative breast cancer progression via the STEAP3-dependent CDK16-JAK1 activation

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by high recurrence rates and limited treatments beyond chemotherapy. The interplay between tumor cells and the tumor microenvironment plays a critical role in TNBC progression, with copper homeostasis emerging as a key regulator of this dynamic niche. Our previous study indicated elevated serum copper as a predictor of poor prognosis for TNBC patients, but its specific role and underlying mechanisms remains to be elucidated. Herein, notable upregulation of STEAP3 was found in high-copper TNBC patients and significantly associated with poor prognosis. The intracellular copper level markedly increased upon STEAP3 overexpression and decreased following STEAP3 knockdown. Through comprehensive in vitro and in vivo experiments, we proved that copper facilitated cell proliferation, migration, xenograft tumor growth and lung metastasis, which were inhibited by copper chelator tetrathiomolybdate. Mechanistically, copper directly bound to CDK16 kinase, leading to its activation, in turn enhanced CDK16 binding and subsequently activating JAK1 kinase to upregulate transcription of c-Myc and cyclin D1. Critically, targeted knockdown of STEAP3 remarkably inhibited TNBC cells proliferation, migration and xenograft tumor growth. These findings unveil a critical pro-tumorigenic copper-driven pathway-distinct from cuproptosis-operating through STEAP3/copper/CDK16/JAK1 axis, and highlight STEAP3 as a promising therapeutic target for TNBC.