Prolactin (PRL) promotes tumor growth, as recently highlighted by the spontaneous appearance of prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. Human (h)PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all PRL receptor antagonists obtained to date exhibit partial agonism, limiting their therapeutic use as full antagonists. This is the case for the first generation antagonists (the prototype of which is G129R-hPRL) that we developed ten years ago, which display antagonistic activity in some, but not all in vitro bioassays, and fail to inhibit PRL activity in transgenic mice expressing this analog. We recently developed 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 assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as demonstrated by their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland and prostate). Finally, using transgenic mice specifically expressing PRL in the prostate, which have constitutively activated signaling cascades and prostate hyperplasia, these new PRL analogs are able to completely revert PRL-activated events to basal levels. These second generation antagonists are good candidates to be used as inhibitors of the growth-promoting actions of hPRL.
