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Submitted on December 29, 2006
Accepted on March 26, 2007
Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Dept. of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057; INSERM, Unit 808, Laboratory "PRL, GH and Tumors", F-75015, France and University Paris Descartes, Faculty of Medicine Rene Descartes, Paris 5- Necker site, Paris, France; ISIS Pharmaceuticals, Carlsbad, CA 92008; Department of Urology, University of Basel, Basel, Switzerland; Dept. of Surgery, University Hospital of Turku, Turku, Finland, Dept. of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere 33520, Finland. Institute for Pathology, Basel CH-4003, Switzerland
* To whom correspondence should be addressed. 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 Stat5a/5b via activation of Jak2. 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 have 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 transcription factor 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-Jak2-Stat5 signaling pathway in advanced prostate cancer.
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