Hung, A.C., Lo, S., Hou, M.F., Lee, Y.C., Tsai, C.H., Chen, Y.Y., Liu, W., Su, Y.H., Lo, Y.H., Wang, C.H., Wu, S.C., Hsieh, Y.C., Hu, S.C., Tai, M.H., Wang, Y.M., Yuan, S.F. (2016) Extracellular Visfatin-Promoted Malignant Behavior in Breast Cancer Is Mediated Through c-Abl and STAT3 Activation. Clinical cancer research : an official journal of the American Association for Cancer Research. 22(17):4478-90.
Purpose Visfatin is an adipocytokine involving in cellular metabolism, inflammation, and cancer. This study investigated the roles of extracellular visfatin in breast cancer, and explored underlying mechanisms in clinical and experimental settings.
Experimental design Associations of serum visfatin with clinicopathological characteristics and patient survival were assessed with Cox regression models and Kaplan-Meier analyses. Effects of extracellular visfatin on cultured breast cancer cells were examined, followed by in vivo investigation of tumor growth and metastasis in xenograft animal models. Imatinib and Stattic were utilized to inhibit c-Abl and STAT3 activation, respectively.
Results Breast cancer patients with high serum visfatin levels were associated with advanced tumor stage, increased tumor size and lymph node metastasis, and poor survival. Elevated phosphorylation of c-Abl and STAT3 in breast tumor tissues were correlated with high serum visfatin levels in patients. Visfatin-promoted in vitro cell viability and metastatic capability were suppressed by imatinib (c-Abl inhibitor) and Stattic (STAT3 inhibitor). Increased in vivo cell invasiveness was observed in zebrafish xenografted with visfatin-pretreated breast cancer cells. Tumor growth and lung metastasis occurred in visfatin-administered mice xenografted with breast cancer cells. Tail vein-injected mice with visfatin-pretreated breast cancer cells showed increased lung metastasis, which was suppressed by imatinib.
Conclusions Serum visfatin levels in breast cancer patients reveal potential prognostic values, and our findings that visfatin promoted breast cancer through activation of c-Abl and STAT3 may provide an important molecular basis for future design of targeted therapies that take into account of different serum visfatin levels in breast cancer.