Development of pure prolactin receptor antagonists.
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.
Bernichtein
Sophie
S
INSERM Unit 584, Hormone Targets, 156 Rue de Vaugirard, 75730 Paris Cedex 15, France.
Kayser
Christine
C
Dillner
Karin
K
Moulin
Stéphanie
S
Kopchick
John J
JJ
Martial
Joseph A
JA
Norstedt
Gunnar
G
Isaksson
Olle
O
Kelly
Paul A
PA
Goffin
Vincent
V
D020816:Amino Acid Motifs; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008894:Milk Proteins; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D011233:Precipitin Tests; D011388:Prolactin / Q000737:chemistry* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011863:Radioimmunoassay; D051381:Rats; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D006728:Hormones; D008894:Milk Proteins; D011981:Receptors, Prolactin; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011388:Prolactin