ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway

Breast cancer has the highest global incidence and mortality rates among all cancer types. Abnormal expression of the Annexin family has been observed in different malignant tumors, including upregulated ANXA9 in breast cancer. We found highly expressed ANXA9 in metastatic breast cancer tissues, which is correlated with breast cancer progression. In vitro, the functional experiments indicated ANXA9 influenced breast cancer proliferation, motility, invasion, and apoptosis; in vivo, downregulation of ANXA9 suppressed breast cancer xenograft tumor growth and lung metastasis. Mechanically, on one side, we found that ANXA9 could mediate S100A4 and therefore regulate AKT/mTOR/STAT3 pathway to participate p53/Bcl-2 apoptosis; on the other side, we found ANXA9 transferred S100A4 from cells into the tumor microenvironment and mediated the excretion of cytokines IL-6, IL-8, CCL2, and CCL5 to participate angiogenesis via self- phosphorylation at site Ser2 and site Thr69. Our findings demonstrate significant involvement of ANXA9 in promoting breast cancer progression, thereby suggesting that therapeutic intervention via targeting ANXA9 may be effective in treating metastatic breast cancer.