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Prostatic Intraepithelial Neoplasia in Mice with Conditional Disruption of the Retinoid X Receptor Allele in the Prostate Epithelium¹

Departments of Biochemistry and Molecular Biology [J. H., T. M., H. M. S., P. R-B.], Pathology [W. C. P., A. C. K., J. W., P. R-B.], and Cell and Neurobiology [H. M. S.], Keck School of Medicine, University of Southern California, Los Angeles, California 90033; Center for Comparative Medicine, University of California-Davis, Davis, California 95616 [R. D. C.]; and Department of Pathology, The University of Iowa, Iowa City, Iowa 52242 [M. B. C.]

Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor (RXR) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXR function. There was also a significant change in the profile of secretory proteins in the RXR mutant prostate relative to littermate controls with intact RXR allele. Histopathologically, homozygous RXR-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at 10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10–15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXR, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.

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