Daidzein Suppresses Tumor Necrosis Factor-alpha Induced Migration and Invasion by Inhibiting Hedgehog/Gli1 Signaling in Human Breast Cancer Cells

Abstract

In breast cancer, the cytokine tumor necrosis factor-alpha (TNF-alpha) induces cell invasion, although the molecular basis of it has not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-alpha induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-alpha induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-alpha activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-alpha induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-alpha induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion.