Autocrine pro-legumain promotes breast cancer metastasis via binding to integrin αvβ3

Tumor metastasis is the leading cause of cancer-associated mortality. Unfortunately, the underlying mechanism of metastasis is poorly understood. Expression of legumain (LGMN), an endo-lysosomal cysteine protease, positively correlates with breast cancer metastatic progression and poor prognosis. Here, we report that LGMN is secreted in the zymogen form by motile breast cancer cells. Through binding to cell surface integrin alpha v beta 3 via an RGD motif, the autocrine pro-LGMN activates FAK-Src-RhoA signaling in cancer cells and promotes cancer cell migration and invasion independent of LGMN protease activity. Either silencing LGMN expression or mutationally abolishing pro-LGMN-alpha v beta 3 interaction significantly inhibits cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Finally, we developed a monoclonal antibody against LGMN RGD motif, which blocks pro-LGMN-alpha v beta 3 binding, and effectively suppresses cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Thus, disruption of pro-LGMN-integrin alpha v beta 3 interaction may be a potentially promising strategy for treating breast cancer metastasis.

Automated summary

This study reveals that legumain (LGMN) activates FAK-Src-RhoA signaling through binding to integrin alpha v beta 3 on the cell surface, promoting cancer cell migration and invasion independent of its protease activity. Silencing LGMN expression or disrupting the interaction between LGMN and integrin alpha v beta 3 significantly inhibits breast cancer cell migration and invasion. Moreover, a monoclonal antibody against the RGD motif of LGMN effectively blocks LGMN-integrin alpha v beta 3 binding and suppresses cancer cell migration and invasion.