KISS1 and Its G Protein-Coupled Receptor (GPR54) in Cancer Progression and Metastasis

Activation of G-protein coupled receptor 54 (GPR54) signaling generated by kisspeptins (endogenous GPR54 ligands encoded by KISS1 gene) has been known to regulate puberty and to suppress cancer metastasis. However, an endogenous GPR54 signaling in cancer progression is still unclear. This study demonstrates that an autocrine GPR54 signaling regulates breast cancer progression and metastasis. When MMTV-PyMT mice were crossed with Gpr54 heterozygous mice, Gpr54 heterozygosity attenuated PyMT-inudced breast cancer progression, including tumorigenesis and metastasis. Likewise, Gpr54 heterozygosity retarded in vitro primary tumor cell proliferation, migration, anchorage-independent growth, and in vivo tumor growth in SCID mice. Furthermore, the anchorage-independent growth was linked to dosage-depdent Gpr54 regulation of RhoA. Human KISS1 and GPR54 were abundantly expressed in benign breast tissue. In MCF10A normal human breast epthelial cells, knockdown of GPR54 or inactivation of RhoA reduced Ras-induced anchorage-independent growth, while consistutively active RhoA recovered Ras-induced tumorigeneity in GPR54-silenced cells. Therefore, this study suggests that autocrine GPR54 signaling via RhoA is sufficient for breast tumorigenesis. The major population of human breast cancer is estrogen receptor-positive (ER?). This study further demonstrates that a loss of autocrine GPR54 signaling in non-metastatic ER? breast cancer cells induces estrogen-independent tumor growth and metastasis with a morphological change. In MCF7 non-metastatic ER? human breast cancer cells, loss of autocrine GPR54 signaling by knockdown of KISS1 or GPR54 caused a morphological change with an alteration of epithelial-to-mesenchymal (EMT) gene expression. Accordingly, silencing of GPR54 signaling by knockdown with KISS1 shRNA or GPR54 shRNA reduced cell proliferation, but enhanced cell motility and anchorage-independent growth. In addition, loss of autocrine GPR54 signaling caused E?-insensitivity. In xenograft tumor growth assays, the lack of autocrine GPR54 signaling caused E?-indpendent tumor growth. In the experimental metastasis mouse model, loss of autocrine GPR54 signaling promoted pulmonary metastasis. Thus, those data indicate that loss of autocrine GPR54 signaling causes estrogen-independent tumor growth and metastasis by promoting epithelial-to-mesenchymal transition (EMT). Altogether, this study demonstrates that the autocrine KISS1-GPR54 signaling is sufficient for breast tumorigenesis and for suppressing ER? breast cancer metastasis.