The KLF5 (Kruppel-like factor 5) transcription factor is specifically expressed in a subset of estrogen receptor alpha-negative breast cancers. Although KLF5 promotes breast cancer cell cycle progression, survival, and tumorigenesis, the mechanism by which KLF5 promotes breast cancer is still not entirely understood. Here, we demonstrate that mPGES1, encoding microsomal prostaglandin E-2 synthase 1 (mPGES1), is a KLF5 direct downstream target gene. KLF5 overexpression or knockdown positively altered the levels of mPGES1 mRNA and protein in multiple breast cell lines. 12-O-Tetradecanoylphorbol-13-acetate induced the expression of both KLF5 and mPGES1 in dosage- and time-dependent manners. The induction of KLF5 was essential for 12-O-tetradecanoylphorbol-13-acetate to induce mPGES1 expression. Additionally, KLF5 bound to the mPGES1 gene proximal promoter and activated its transcription. Both KLF5 and mPGES1 promoted prostaglandin E-2 production; regulated p21, p27, and Survivin downstream gene expression; and likewise stimulated cell proliferation. Overexpression of mPGES1 partially rescued the KLF5 knockdown-induced downstream gene expression changes and growth arrest in MCF10A cells. Finally, we demonstrate that the expression of mPGES1 was positively correlated with the estrogen receptor alpha/progesterone receptor/HER2 triple-negative status. These findings suggest that mPGES1 is a target gene of KLF5, making it a new biomarker and a potential therapeutic target for triple-negative breast cancers.