RNA interference-directed silencing of VPAC1 receptor inhibits VIP effects on both EGFR and HER2 transactivation and VEGF secretion in human breast cancer cells

We used small-interference RNA (siRNA) to explore the mechanisms of some vasoactive intestinal peptide (VIP) actions on human breast cancer cells. Transfection of estrogen-dependent (T47D) and estrogen-independent (MDA-MB-468) breast cancer cells with VPAC1-receptor siRNA completely abolished VIP stimulatory effect on secretion of the main angiogenic factor, vascular endothelial growth factor (VEGF), and transactivation of epidermal growth factor receptor (EGFR or HER1) and HER2, two members of HER family of tyrosine-kinase receptors. The silencing procedure suggested the involvement of EGFR and HER2 transactivation in VIP-stimulated VEGF secretion. It was further supported by blocking tyrosine kinase activity by the selective HER inhibitors AG-1478 (EGFR) and AG-825 (HER2). Results give value to the specific signaling of VIP through VPAC1 receptor in human breast cancer cells and support the potential use of VPAC1-receptor antagonists in combined targeted therapies for breast cancer. Molecular therapies involving RNA interference of VPAC1-receptor expression could also be considered.

► Proliferation was impaired in VPAC1-receptor siRNA transfected breast cancer cells.
► VPAC1-receptor silencing abolished VIP stimulation of VEGF165 secretion.
► VPAC1-receptor silencing abolished VIP transactivation of EGFR and HER2.
► EGFR and HER2 transactivation are likely involved in VIP-stimulated VEGF secretion.