This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goffin, V. Articles by Kelly, P. A. Search for Related Content PubMed PubMed Citation Articles by Goffin, V. Articles by Kelly, P. A.

Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists

Institut National de la Santé et de la Recherche Médicale, Unit 584 (V.G., S.B., P.T., P.A.K.), Paris Cedex 15, France; Université René Descartes-Paris V (V.G., S.B., P.T., P.A.K.), 75730, Paris Cedex 15, France; and Service d’Endocrinologie et Médecine de la Reproduction (P.T.), Hôpital Necker-Enfants Malades, 75743 Paris Cedex 15, France

Correspondence: Address all correspondence and requests for reprints to: Dr. Vincent Goffin, Institut National de la Santé et de la Recherche Médicale Unit 584, Faculté de Médecine Necker, 156, rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: goffin{at}necker.fr

There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, 1–9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.

This article has been cited by other articles:

				D. Giacomini, M. Paez-Pereda, J. Stalla, G. K. Stalla, and E. Arzt Molecular Interaction of BMP-4, TGF-{beta}, and Estrogens in Lactotrophs: Impact on the PRL Promoter Mol. Endocrinol., July 1, 2009; 23(7): 1102 - 1114. [Abstract] [Full Text] [PDF]

				A. Plotnikov, B. Varghese, T. H. Tran, C. Liu, H. Rui, and S. Y. Fuchs Impaired Turnover of Prolactin Receptor Contributes to Transformation of Human Breast Cells Cancer Res., April 1, 2009; 69(7): 3165 - 3172. [Abstract] [Full Text] [PDF]

				L. M. Arendt, T. L. Grafwallner-Huseth, and L. A. Schuler Prolactin-Growth Factor Crosstalk Reduces Mammary Estrogen Responsiveness Despite Elevated ER{alpha} Expression Am. J. Pathol., March 1, 2009; 174(3): 1065 - 1074. [Abstract] [Full Text] [PDF]

				B. Varghese, H. Barriere, C. J. Carbone, A. Banerjee, G. Swaminathan, A. Plotnikov, P. Xu, J. Peng, V. Goffin, G. L. Lukacs, et al. Polyubiquitination of Prolactin Receptor Stimulates Its Internalization, Postinternalization Sorting, and Degradation via the Lysosomal Pathway Mol. Cell. Biol., September 1, 2008; 28(17): 5275 - 5287. [Abstract] [Full Text] [PDF]

				A. Plotnikov, Y. Li, T. H. Tran, W. Tang, J. P. Palazzo, H. Rui, and S. Y. Fuchs Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3{beta} Impairs Degradation of Prolactin Receptor Cancer Res., March 1, 2008; 68(5): 1354 - 1361. [Abstract] [Full Text] [PDF]

				P. W. Harvey, D. J. Everett, and C. J. Springall Adverse effects of prolactin in rodents and humans: breast and prostate cancer J Psychopharmacol, March 1, 2008; 22(2_suppl): 20 - 27. [Abstract] [PDF]

				G. Swaminathan, B. Varghese, C. Thangavel, C. J Carbone, A. Plotnikov, K G S. Kumar, E. M Jablonski, C. V Clevenger, V. Goffin, L. Deng, et al. Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2 J. Endocrinol., February 1, 2008; 196(2): R1 - R7. [Abstract] [Full Text] [PDF]

				N. Ben-Jonathan, C. R. LaPensee, and E. W. LaPensee What Can We Learn from Rodents about Prolactin in Humans? Endocr. Rev., February 1, 2008; 29(1): 1 - 41. [Abstract] [Full Text] [PDF]

				J.-B. Jomain, E. Tallet, I. Broutin, S. Hoos, J. van Agthoven, A. Ducruix, P. A. Kelly, B. B. Kragelund, P. England, and V. Goffin Structural and Thermodynamic Bases for the Design of Pure Prolactin Receptor Antagonists: X-RAY STRUCTURE OF Del1-9-G129R-hPRL J. Biol. Chem., November 9, 2007; 282(45): 33118 - 33131. [Abstract] [Full Text] [PDF]

				L. M. Neilson, J. Zhu, J. Xie, M. G. Malabarba, K. Sakamoto, K.-U. Wagner, R. A. Kirken, and H. Rui Coactivation of Janus Tyrosine Kinase (Jak)1 Positively Modulates Prolactin-Jak2 Signaling in Breast Cancer: Recruitment of ERK and Signal Transducer and Activator of Transcription (Stat)3 and Enhancement of Akt and Stat5a/b Pathways Mol. Endocrinol., September 1, 2007; 21(9): 2218 - 2232. [Abstract] [Full Text] [PDF]

				A. Dagvadorj, S. Collins, J.-B. Jomain, J. Abdulghani, J. Karras, T. Zellweger, H. Li, M. Nurmi, K. Alanen, T. Mirtti, et al. Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway Endocrinology, July 1, 2007; 148(7): 3089 - 3101. [Abstract] [Full Text] [PDF]

				O. Eyal, J.-B. Jomain, C. Kessler, V. Goffin, and S. Handwerger Autocrine Prolactin Inhibits Human Uterine Decidualization: A Novel Role for Prolactin Biol Reprod, May 1, 2007; 76(5): 777 - 783. [Abstract] [Full Text] [PDF]

				S. S. Tworoger, A. H. Eliassen, P. Sluss, and S. E. Hankinson A Prospective Study of Plasma Prolactin Concentrations and Risk of Premenopausal and Postmenopausal Breast Cancer J. Clin. Oncol., April 20, 2007; 25(12): 1482 - 1488. [Abstract] [Full Text] [PDF]

				A. Diogenes, A. M. Patwardhan, N. A. Jeske, N. B. Ruparel, V. Goffin, A. N. Akopian, and K. M. Hargreaves Prolactin Modulates TRPV1 in Female Rat Trigeminal Sensory Neurons J. Neurosci., August 2, 2006; 26(31): 8126 - 8136. [Abstract] [Full Text] [PDF]

				C. Manhes, C. Kayser, P. Bertheau, B. Kelder, J. J Kopchick, P. A Kelly, P. Touraine, and V. Goffin Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma. J. Endocrinol., August 1, 2006; 190(2): 271 - 285. [Abstract] [Full Text] [PDF]

				M. P. Gillam, M. E. Molitch, G. Lombardi, and A. Colao Advances in the Treatment of Prolactinomas Endocr. Rev., August 1, 2006; 27(5): 485 - 534. [Abstract] [Full Text] [PDF]

				P W Harvey, D J Everett, and C J Springall Hyperprolactinaemia as an adverse effect in regulatory and clinical toxicology: role in breast and prostate cancer Human and Experimental Toxicology, July 1, 2006; 25(7): 395 - 404. [Abstract] [PDF]

				A. Mukherjee, W. D. J. Ryder, A. Jostel, and S. M. Shalet Prolactin Deficiency Is Independently Associated with Reduced Insulin-Like Growth Factor I Status in Severely Growth Hormone-Deficient Adults J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2520 - 2525. [Abstract] [Full Text] [PDF]

				L. M. Arendt, T. A. Rose-Hellekant, E. P. Sandgren, and L. A. Schuler Prolactin Potentiates Transforming Growth Factor {alpha} Induction of Mammary Neoplasia in Transgenic Mice Am. J. Pathol., April 1, 2006; 168(4): 1365 - 1374. [Abstract] [Full Text] [PDF]

				A. Glezer, C. R. J. Soares, J. G. Vieira, D. Giannella-Neto, M. T. C. P. Ribela, V. Goffin, and M. D. Bronstein Human Macroprolactin Displays Low Biological Activity via Its Homologous Receptor in a New Sensitive Bioassay J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1048 - 1055. [Abstract] [Full Text] [PDF]

				F. Y. Ma, G. M. Anderson, T. D. Gunn, V. Goffin, D. R. Grattan, and S. J. Bunn Prolactin Specifically Activates Signal Transducer and Activator of Transcription 5b in Neuroendocrine Dopaminergic Neurons Endocrinology, December 1, 2005; 146(12): 5112 - 5119. [Abstract] [Full Text] [PDF]