PKCα-mediated cGAS nuclear translocation stabilizes β-catenin, driving triple-negative breast cancer metastasis.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies and a high propensity for metastasis, which remains a major challenge in patient outcomes. While 2'3'-cyclic GMP-AMP synthase (cGAS) is known for its canonical cytoplasmic immune sensing, its non-canonical nuclear functions, particularly in cancer metastasis, are poorly understood. The Wnt/β-catenin signaling pathway is a well-established driver of cancer progression and metastasis, making its regulation a critical area of investigation for novel therapeutic strategies in TNBC.

Researchers investigated the role of nuclear cGAS in triple-negative breast cancer (TNBC) metastasis using in vitro cell models and in vivo preclinical models. They examined PKCα phosphorylation of cGAS at Ser120 and its impact on nuclear translocation using immunofluorescence and co-immunoprecipitation assays. The study also assessed the interaction between cGAS, β-catenin, and TRIM33 to understand β-catenin stability. Furthermore, the efficacy of Therapeutic transactivator of transcription (TAT) peptides in inhibiting cGAS phosphorylation and reducing metastasis was evaluated in vivo. Clinical relevance was established by analyzing nuclear cGAS expression in TNBC patient cohorts.

The study revealed that Protein kinase C alpha (PKCα) phosphorylates cGAS at Ser120, a critical event facilitating cGAS's nuclear translocation. Once in the nucleus, cGAS directly disrupts the interaction between β-catenin and tripartite motif-containing protein 33 (TRIM33), a known E3 ubiquitin ligase. This disruption prevents β-catenin ubiquitination, leading to its stabilization and subsequent activation of Wnt/β-catenin signaling, thereby promoting metastasis. This establishes PKCα as a key upstream regulator of this non-canonical, STING-independent cGAS-driven metastatic pathway. > Therapeutic TAT peptides designed to inhibit cGAS phosphorylation significantly reduce metastasis in preclinical models. Clinically, elevated nuclear cGAS expression was strongly associated with increased metastasis in TNBC patient cohorts, underscoring its prognostic value and the clinical relevance of the PKCα-cGAS-TRIM33 axis.