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Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan
¹ Department of Molecular Medical Technology, Tohoku University School of Medicine, Sendai, Japan
² Department of Medicine, Tohoku University School of Medicine, Sendai, Japan
³ Department of Surgery, Tohoku University School of Medicine, Sendai, Japan

(Requests for offprints should be addressed to T Suzuki; Email: t-suzuki{at}patholo2.med.tohoku.ac.jp)

It has been reported that agonists of peroxisome proliferator-activated receptor (PPAR) inhibit proliferation of breast carcinoma cells, but the biological significance of PPAR remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPAR in 238 human breast carcinoma tissues. PPAR immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) , ERß, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPAR immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPAR immunoreactivity was an independent prognostic factor for overall survival in ER-positive patients. We then examined possible mechanisms of modulation by PPAR on estrogenic actions in MCF-7 breast carcinoma cells. A PPAR activator, 15-deoxy-^12,14- prostaglandin J₂ (15d-PGJ₂), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPAR 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 PPAR is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.

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