Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line

Overexpression of neuropeptide Y (NPY) and its receptor system has been reported in various types of cancers. NPY Y5 receptor (Y5R) has been implicated in cell growth and angiogenesis. However, the role of Y5R in breast cancer is unknown. To identify the role of Y5R in breast cancer, we screened several breast cancer cell lines to examine the expression of Y5R and its function in breast cancer. All screened cell lines express both Y1 receptor and Y5R except BT-549, which expresses mainly Y5R. Binding studies showed that NPY, Y5R-selective agonist peptide, and Y5R-selective antagonist (CGP71683A) displaced 125I-PYY binding in BT-549 cell membranes in a dose-dependent manner. The displacement studies revealed the presence of two binding sites in Y5R with IC50 values of 29 pmol/L and 531 nmol/L. NPY inhibited forskolin-stimulated cyclic AMP accumulation with an IC50 value of 52 pmol/L. NPY treatment of BT-549 cells induced extracellular signal-regulated kinase phosphorylation but did not alter intracellular calcium. Y5R activation stimulates BT-549 cell growth, which is inhibited by CGP71683A, pertussis toxin, and extracellular signal-regulated kinase blockade. CGP71683A alone induced cell death in a time- and dose-dependent manner in Y5R-expressing cells. The stimulation of MDA MB-231 cell migration by NPY is inhibited by CGP71683A. Together, our results suggest that Y5R plays an important role in cancer cell growth and migration and could be a novel therapeutic target for breast cancer. Mol Cancer Res; 8(4); 604–14. ©2010 AACR.