Tumor microenvironment can convert the host immune responses to favor tumor growth. However, the underlying mechanisms of how tumor cells educate host immunity are still largely unknown. We found that Th17 cells were increased in the peripheral blood, spleen and tumor tissues of mammary gland tumor-bearing mice. Th17 cell survival factor, IL-23 was overexpressed in tumor tissues isolated from both mouse and human breast cancer patients. Soluble molecules secreted from tumor cells but not normal breast epithelial cells induced IL-23 protein secretion in DCs via induction of the p19 mRNA expression. Our data further indicates that tumor-secreted PGE2 via its receptor EP2 and EP4 enhanced IL-23 p19 gene transcription through binding to the cAMP-response element in the p19 promoter. Blocking PGE2 synthesis by NS398, a Cox2 inhibitor, abrogated the enhancement of p19 expression both in vitro and in vivo. Furthermore, blocking PKA by H89 completely abrogated the inductive effects of tumor conditioned medium and PGE2 on p19 transcription. In line with this finding, cAMP active analog, Forskolin mimics the PGE2 effect. Taken together, our results indicate that tumor-secreted PGE2 differentially induce IL-23 but not IL-12 production in the tumor microenvironment which could promote Th17 cell expansion. This inductive effect is mediated through cAMP/PKA signaling transduction pathway by increasing p19 transcription.