Human formyl peptide receptors (FPRs) 1, 2 and 3 comprise a small family of seven transmembrane domain G protein-coupled receptors that have a well established role in innate immunity and inflammation. Recognition of bacteria-derived N-formyl peptides by the FPRs activates the microbicidal, secretory, and chemotactic functions of phagocytic cells in vitro. Extracellular Annexin-A1, and peptides derived from it, also act as agonists of FPR2. FPR1 and FPR2 are primarily expressed by monocytes, neutrophils and dendritic cells whereas FPR3 is almost exclusively expressed by activated dendritic cells.
However, FPRs can also be ectopically expressed in certain tumour types such as breast cancer, and our laboratory recently showed that well-characterized agonists for FPR2, including the ANXA1 N-terminal proteolytic product ANXA1(2-26), lipoxin A(4), and the synthetic peptide, Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), stimulated proliferation of MDA-MB-231 breast cancer cells in vitro that was attenuated by incubation with FPR2 antagonists WRW(4) (1μM) or Boc2 (100nM) or by siRNA against FPR2, together suggesting that FPR2 may promote epithelial tumourigenesis.1 TaqMan qPCR demonstrated that both FPR1 and FPR2 mRNAs were expressed by the estrogen receptor negative basal-like cell lines MDA-MB-231 and Hs578T, and that FPR1 was also expressed by the immortal mammary epithelial cell line, MCF10A. To study the role of FPRs in human breast cancer cells in vivo, stable shRNA-mediated knockdown of FPR1 was produced in MCF10A and MDA-MB-231 cells and of FPR2 in MDA-MB-231 cells using the lentiviral pGIPZ vector, which also encodes GFP.
Our laboratory has also acquired C57Bl/6 mice null for murine Fpr2 (Fpr2-/-) or its endogenous ligand Anxa1 (Anxa1-/-). This will permit dissection of the roles of both host-derived and tumour-derived molecules through orthotopic implantation of murine mammary tumour lines such as EO7712 and AT33 , engineered to over-express formyl peptide receptors.