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T Suzuki, S Hayashi, Y Miki, Y Nakamura, T Moriya, A Sugawara, T Ishida, N Ohuchi, and H Sasano

It has been reported that agonists of peroxisome proliferator-activated receptor γ (PPARγ) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARγ remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARγ in 238 human breast carcinoma tissues. PPARγ immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) α, ERβ, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARγ immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARγ immunoreactivity was an independent prognostic factor for overall survival in ERα-positive patients. We then examined possible mechanisms of modulation by PPARγ on estrogenic actions in MCF-7 breast carcinoma cells. A PPARγ activator, 15-deoxy-Δ12,14- prostaglandin J2 (15d-PGJ2), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARγ antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogen-responsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ2 in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ2 significantly inhibited estrogen-mediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARγ is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.