title: GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
abstract: Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.
authors: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.
authors: Mateusz
authors: M
authors: Zajac
authors: Jeffrey
authors: J
authors: Law
authors: Dragana Donna
authors: DD
authors: Cvetkovic
authors: Macarena
authors: M
authors: Pampillo
authors: Lindsay
authors: L
authors: McColl
authors: Cynthia
authors: C
authors: Pape
authors: Gianni M
authors: GM
authors: Di Guglielmo
authors: Lynne M
authors: LM
authors: Postovit
authors: Andy V
authors: AV
authors: Babwah
authors: Moshmi
authors: M
authors: Bhattacharya
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D059648:Kisspeptins / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1
chemical_list: C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9