Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity.

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin-2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5-year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell-like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP-S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2-LATS2-YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy.