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[Cancer Research 59, 5737-5744, November 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 5737-5744, November 15, 1999]
© 1999 American Association for Cancer Research

Endocrinology

Human Uterine Leiomyomata Express Higher Levels of Peroxisome Proliferator-activated Receptor {gamma}, Retinoid X Receptor {alpha}, and all-trans Retinoic Acid Than Myometrium

John C. M. Tsibris1, Kathy B. Porter2, Allahyar Jazayeri2, Georg Tzimas3, Heinz Nau4, Hong Huang5, Khatuna Kuparadze6, Gregory W. Porter2, William F. O’Brien and William N. Spellacy

Departments of Obstetrics and Gynecology [J. C. M. T., K. B. P., A. J., H. H., K. K., G. W. P., W. F. O., W. N. S.] and Biochemistry and Molecular Biology [J. C. M. T.], University of South Florida, Tampa, Florida 33606, and Institute for Clinical Pharmacology and Toxicology, Free University of Berlin, D-14195 Berlin, Germany [G. T., H. N.]

Uterine leiomyomata are the main indication for a hysterectomy in the United States and occur in 25% of women >35 years. Because uterine leiomyomata can form when ovariectomized guinea pigs are exposed to estradiol and retinoic acids, we tested whether human leiomyomata had high levels of retinoic acids and related nuclear receptors. Compared with normal human myometrium, leiomyomata had 3- to 5-fold higher levels of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), retinoid X receptor {alpha} proteins, and all-trans retinoic acid, but only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was undetectable in either leiomyomata or myometrium. PPAR{gamma} mRNA levels were lower in leiomyomata than myometrium, but only during the luteal phase of the cycle. A PPAR{gamma} agonist, troglitazone, was given to guinea pigs along with estradiol and all-trans retinoic acid and produced the largest leiomyomata seen to date in this model. By contrast, no tumors formed when troglitazone was given alone or with estradiol or when troglitazone was given with estradiol and 9-cis retinoic acid. New therapies for human leiomyomata may emerge by combining antagonists for PPAR{gamma} and retinoid X receptor {alpha} with selective estrogen receptor modulators.




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