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J. Biol. Chem., Vol. 278, Issue 38, 35988-35999, September 19, 2003

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Development of Pure Prolactin Receptor Antagonists^*

Sophie Bernichtein  , Christine Kayser , Karin Dillner ¶, Stéphanie Moulin , John J. Kopchick ||, Joseph A. Martial **, Gunnar Norstedt ¶, Olle Isaksson , Paul A. Kelly  and Vincent Goffin  

From the INSERM Unit 584, Hormone Targets, 156 Rue de Vaugirard, 75730 Paris Cedex 15, France, the ^¶Department of Molecular Medicine, Karolinska Institute, Karolinska sjukhuset L801, 171 76 Stockholm, Sweden, ^||Edison Biotechnology Institute, Molecular and Cellular Biology Program, and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, ^**Laboratory of Molecular Biology and Genetic Engineering, Allée du 6 Août, University of Liège, 4000 Sart-Tilman, Belgium, and the Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg University, SE 41345 Göteborg, Sweden

Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.

Received for publication, May 30, 2003 , and in revised form, June 23, 2003.

^* This work was supported in part by Inserm and the Comité de Paris de la Ligue Nationale Contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported initially by a student fellowship from the Ministry of Research and Technology of France and then by fellowships from Fondation pour la Recherche Médicale et la Ligue Nationale Contre le Cancer.

To whom correspondence should be addressed: INSERM Unit 584, Hormone Targets, 156 Rue de Vaugirard, 75730, Paris Cedex 15, France. Tel.: 33-1-40-61-53-10; Fax: 33-1-43-06-04-43; E-mail: goffin{at}necker.fr.

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