Cathepsin G as a central regulator of tumor plasticity and osteolytic metastasis in breast cancer

Breast cancer frequently metastasizes to bone, where osteolytic lesions drive substantial morbidity. We identified Cathepsin G (CTSG), a serine protease expressed by both tumor cells and neutrophils, as being highly upregulated at the tumor-bone interface. However, the distinct contributions of tumor- versus neutrophil-derived CTSG remain poorly defined. To examine the role of CTSG in modulating malignant phenotype, we treated breast cancer cells with recombinant CTSG (rCTSG), which reduced proliferation, induced cell cycle arrest, promoted homotypic aggregation and collective migration; and induced a luminal to basal shift. Modeling tumor-derived CTSG through stable overexpression reproduced these effects and, in vivo, suppressed tumor growth yet paradoxically enhanced osteoclast activation and bone destruction. Immunohistochemical analysis indicated that tumor-derived CTSG reduced proliferation, did not significantly affect apoptosis, and altered epithelial characteristics, particularly at the tumor-bone interface. To assess neutrophil-derived CTSG, we co-cultured breast cancer cells with neutrophils, which similarly inhibited proliferation, promoted aggregation and migration, implicating a paracrine role. Together, our findings position CTSG as a central regulator of tumor phenotype and bone-tumor interactions and highlight it as a potential therapeutic target in breast cancer bone metastasis.