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Prostate Development and Carcinogenesis in Prolactin Receptor Knockout Mice

Cancer Research Program (F.G.R., J.H., M.J.N., S.R.O., C.J.O.), Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, 2010 Sydney, Australia; Department of Physiology (J.K., K.D., H.W., J.T.), Research Center for Endocrinology and Metabolism, Göteborg University, S-405 30 Göteborg, Sweden; Institut National de la Santé et de la Recherche Médicale Unité 584 (P.A.K.), Faculté de Médecine Necker-Enfants Malades, 75730 Paris, France; and Laboratory of Cell Regulation and Carcinogenesis (J.G.), National Cancer Institute, Bethesda, Maryland 20892-1402

Address all correspondence and requests for reprints to: Dr. Christopher Ormandy, Garvan Institute of Medical Research, 384 Victoria Street Darlinghurst, New South Wales 2010, Australia. E-mail: c.ormandy{at}garvan.org.au.

Hyperprolactinemia results in prostatic hypertrophy and hyperplasia, but it is not known whether prolactin plays an essential role in these processes in the prostate. To address this question, we investigated prostate development, gene expression, and simian virus 40 (SV40)T-induced prostate carcinogenesis in prolactin receptor knockout mice. These animals showed a small increase in dorsolateral and ventral prostate weight but no change in the weight of the anterior prostate. The dorsal but not ventral or lateral lobes showed a 12% loss of epithelial cells; all other morphological parameters were normal. The area of SV40T-induced prostate intraepithelial neoplasia was reduced by 28% in the ventral lobe but not the dorsal lobe, and no tumors were seen in 20 prolactin receptor knockout animals, compared with 1 of 11 detected in wild-type and 4 of 21 found in heterozygous animals. Oligonucleotide microarrays were used to identify essential transcriptional roles of prolactin and revealed a small set of genes with decreased expression involved in sperm/oocyte interaction and copulatory plug formation. Infertility or reduced fertility was apparent in these animals. These findings establish essential though subtle roles for prolactin in the regulation of prostate morphology, gene expression, SV40T-induced neoplasia, and reproductive function.

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