Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-γ (PPARγ) inactivation are linked to increased risk of human breast cancer. The purpose of our study was to examine the relationship between COX-2 (with the resulting prostaglandins E2, PGE2) and PPARγ (and its natural endogenous ligand 15-Deoxy-Δ12,14-prostaglandin J2, 15d-PGJ2) at various stages during the development of human breast cancer and its progression to metastasis. Human breast tissue specimens were collected from normal breasts or from individuals with fibrocystic disease and served as controls (n = 22). Tissues were also collected from uninvolved (n = 25), tumor (n = 25) and lymph node metastasis (n = 15) regions from breast cancer patients. COX-2 and PPARγ mRNA expression were increased and downregulated, respectively, in tissues from cancer patients compared to controls. Metastatic tissues tended to have higher alterations compared to non-metastatic tissues (p < 0.05). These altered expressions in COX-2 and PPARγ were paralleled by increases in the tissue levels of PGE2 and decreases in 15d-PGJ2. A significant inverse correlation was found between PGE2 and 15-d-PGJ2 (r = −0.51, p < 0.05). Significant correlations (p < 0.05) were also obtained between COX-2 and PPARγ mRNA (inverse, r = −0.72) and between COX-2 and PGE2 (direct, r = 0.68). Increases in COX-2 mRNA expression and levels of PGE2 and down-regulation of PPARγ mRNA expression and 15d-PGJ2 levels were characterized as predictors of breast cancer risk (p < 0.05). Our results suggest that the altered expression of COX-2 and PPARγ and the subsequent modulation in the tissue levels of PGE2 and 15-d-PGJ2 may influence the development of human breast cancer and its progression to metastasis. © 2002 Wiley-Liss, Inc.