Prostate-specific G-protein-coupled receptor (PSGR), a member of the olfactory subfamily of G-protein-coupled receptors, is specifically expressed in human prostate tissue and overexpressed in prostate cancer (PCa). This expression pattern suggests a possible role in PCa initiation and progression. We developed a PSGR transgenic mouse model driven by a probasin promoter and investigated the role of PSGR in prostate malignancy. Overexpression of PSGR induced a chronic inflammatory response that ultimately gave rise to premalignant mouse prostate intraepithelial neoplasia lesions in later stages of life. PSGR-overexpressing LnCaP cells in prostate xenografts formed larger tumors compared with normal LnCaP cancer cells, suggesting a role of PSGR in the promotion of tumor development. Furthermore, we identified nuclear factor-κB (NF-κB) or RELA as a key downstream target activated by PSGR signaling. We also show that this regulation was mediated in part by the phosphatidylinositol-3-kinase/Akt (PI3K/AKT) pathway, highlighting a collaborative role between PI3K/AKT and NF-κB during tumor inflammation downstream of PSGR in the initial phases of prostate disease.Oncogenesis (2014) 3, e114; doi:10.1038/oncsis.2014.29; published online 11 August 2014.