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Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway

Department of Cancer Biology (A.D., J.A., M.T.N.), Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Department of Oncology (S.C., H.L.), Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C. 20057; Institut National de la Santé et de la Recherche Médicale (J.-B.J., V.G.), Unité 808, Laboratory "PRL, GH, and Tumors" and University Paris Descartes, Faculty of Medicine Rene Descartes, Paris 5-Necker site, F-75015 Paris, France; ISIS Pharmaceuticals (J.K.), Carlsbad, California 92008; Department of Urology (T.Z.), University of Basel, CH-4056 Basel, Switzerland; Department of Surgery (M.N.), University Hospital of Turku, 20014 Turku, Finland; Department of Pathology (K.A., T.M.), Institute of Biomedicine, University of Turku, 20520 Turku, Finland; Institute of Medical Technology (T.V.), University of Tampere and Tampere University Hospital, Tampere 33520, Finland; and Institute for Pathology (L.B.), Basel CH-4003, Switzerland

Address all correspondence and requests for reprints to: Marja T. Nevalainen, M.D., Ph.D., Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, BLSB 309B, 233 South 10th Street, Philadelphia, Pennsylvania 19107. E-mail: marja.nevalainen{at}jefferson.edu.

The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (1–9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.

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