Transforming growth factor-β1 attenuates junctional adhesion molecule-A and contributes to breast cancer cell invasion

Transforming growth factor-β1 (TGF-β1) is a potent regulator in promoting the invasion and proliferation of breast cancer cells. Junctional adhesion molecule-A (JAM-A) is a tight junction protein that displays an inverse relationship to cell invasiveness in breast cancer cells. Whether TGF-β1 signaling induces alteration of JAM-A expression leading to cell invasion has not been investigated. In this study, we report that TGF-β1 down-regulated JAM-A expression via its effect on both transcriptional and post-translational regulations of JAM-A, thus inducing cell invasion. On exploring whether TGF-β1 might be the upstream regulator of JAM-A expression, we found that knockdown of TGF-β receptors and canonical Smad signaling could upregulate JAM-A level and inhibit cell invasion in MDA-MB-231 cells. TGF-β1 treatment of MCF-7 cells caused a significant reduction of JAM-A mRNA and protein and induced cell invasion. Delineating the signal mechanisms involved in TGF-β1-mediated JAM-A repression, we found that TGF-β1 significantly inhibited JAM-A gene transcription via the activation of Smads. In addition to Smad activation, we found that involvement of p54 JNK is crucial for post-translational modification of TGF-β1-mediated JAM-A protein degradation. Blockage of JNK pathway by inhibitor could attenuate TGF-β1-induced cell invasion. We provide evidences for the first time that TGF-β1 induces breast cancer cell invasion via TGF-β1-mediated control on JAM-A expression. Identification of JAM-A as a downstream target of TGF-β1 represents a crucial mechanism in cancer progression.