Stimulation of the bradykinin B 1 receptor induces the proliferation of estrogen-sensitive breast cancer cells and activates the ERK1/2 signaling pathway

Kinin peptides exert multiple biological effects by binding to two types of G protein-coupled receptors known as B 1 (B 1 R) and B 2 receptors. Expression of the B 1 R in human breast cancer was recently reported, but up to now the consequences of its stimulation are unknown. Our aims were (1) to investigate the capacity of B 1 R to trigger cell proliferation in breast cancer cells, (2) to explore some of the downstream events occurring after B 1 R stimulation that may be linked to cell proliferation, and (3) to determine whether human breast tumors express potentially active B 1 R assessed by the binding of a radiolabeled agonist. Breast cancer cells expressed both the mRNA and the immunoreactive protein of B 1 R that once stimulated triggered cell proliferation at nanomolar concentrations of the ligand. Inhibitor studies suggested that the proliferative effects depend on the activity of epidermal growth factor receptor and subsequent ERK1/2 mitogen-activated protein kinases phosphorylation. B 1 R binding sites, were detected in 3/4 fibroadenomas, in 4/4 ductal carcinomas in situ and in 11/13 invasive ductal carcinomas. The B 1 R-epidermal growth factor receptor crosstalk may be a key interaction that maintains tumor growth, and antagonism of B 1 R may be a valuable alternative for the treatment of breast cancer.