Targeting Tn Antigen Suppresses Aberrant O‐Glycosylation‐Elicited Metastasis in Breast Cancer

ABSTRACT The Tn antigen, a truncated O‐glycan representing aberrant mucin‐type O‐glycosylation, is frequently observed in human breast cancer. However, the functional role of Tn antigen in breast cancer metastasis remains insufficiently investigated. This study aimed to elucidate the expression profile of Tn antigen in breast cancer and its potential as a therapeutic target for inhibiting metastasis. Immunohistochemical staining was performed to determine the levels of Tn antigen expression in breast cancer tissues and its clinical relevance was analyzed accordingly. Tn‐positive breast cancer cell lines were generated through disruption of the Cosmc gene. The functional roles of Tn antigen in breast cancer metastasis were studied in both in vitro and in vivo models. Western blotting and immunofluorescence staining were employed to investigate the molecular mechanisms by which Tn antigen promotes breast cancer metastasis. Our findings revealed that Tn antigen was prevalent in breast carcinomas, particularly within metastatic lesions. Tn antigen expression was positively correlated with lymph node metastasis and poorer patient survival. Tn antigen‐expressing breast cancer cells exhibited enhanced invasiveness and metastasis, along with significant activation of EMT and FAK signaling pathways. Targeting Tn‐positive cells with HPA ( Helix pomatia agglutinin ) demonstrated the suppression of invasive and metastatic capabilities, EMT program, and FAK signaling in vitro, as well as reduced pulmonary metastasis in a xenotransplant mouse model. This study reveals that Tn antigen‐mediated aberrant O‐glycosylation plays a contributing role in breast cancer metastasis, which may serve as a potential therapeutic target in clinical practice.