Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling

Abstract

BackgroundAstragaloside IV (AS-IV), the major active triterpenoid in Radix Astragali, has shown anti-tumorigenic properties in certain cancers; however, its role in breast cancer remains unclear. The present study investigated the effects of AS-IV on breast cancer in vitro and in vivo and examined the underlying mechanisms. MethodsThe effects of AS-IV on MDA-MB-231 cell proliferation, migration, invasion and metastasis were investigated by MTT and Transwell assays, and western blotting. In addition, an orthotopic mouse tumor model was established for in vivo experiments. ResultsAS-IV inhibited the viability and invasive potential of MDA-MB-231 breast cancer cells, suppressed the activation of the mitogen activated protein kinase (MAPK) family members ERK1/2 and JNK, and downregulated matrix metalloproteases (MMP)-2 and -9. The effects of AS-IV were mediated by the downregulation of Vav3, a guanine nucleotide exchange factor, leading to decreased levels of activated Rac1, a Rho family GTPase. Vav3 overexpression promoted cell proliferation and invasion in vitro, whereas Vav3 silencing had the opposite effects. AS-IV suppressed orthotopic breast tumor growth and metastasis to the lungs, whereas ectopic expression of Vav3 reversed the inhibitory effect of AS-IV on cell viability, invasiveness, MAPK signaling and MMP expression. ConclusionThe present results provide a mechanistic explanation for the antitumor effects of AS-IV and suggest its potential in the treatment of metastatic breast cancer.