PL06 IGF-II and feto-placental growth

Prolactin was discovered more than 80 years ago. It is currently viewed by clinical endocrinologists as a hormone of pituitary origin, whose biological actions relate exclusively to lactation and reproductive functions, for which any genetic disorder is yet to be identified, and whose unique associated pathology is hyperprolactinemia, which is efficiently cured using dopamine agonists. There is no debate about these established facts. However, experimental and clinical studies performed during the past decade have considerably broadened our perception of prolactin biology: i. there is now clear epidemiological evidence supporting that circulating prolactin is a risk factor for breast cancer, although the actual mechanisms of action and outcome of prolactin signalling on breast tumorigenesis and disease progression remain a matter of debate (and of intense investigation), ii. in addition to the endocrine (circulating) hormone, locallyproduced prolactin has been documented in various human tissues such as the mammary gland and the prostate, where it is assumed to act via autocrine/paracrine loop; this local mechanism of action may be amplified in tumor contexts due to prolactin and/or prolactin receptor over-expression, iii. we recently reported the first genetic, gain-of-function variant of the prolactin receptor, that may act as an inherited genetic modifier of benign and/or malignant tumorogenesis, iv. we have engineered human prolactin variants acting as pure competitive antagonists of the prolactin receptor, and we have demonstrated their ability to down-regulate the actions triggered by local prolactin as well as by the constitutively active receptor variant in various experimental models; these compounds thus represent a novel class of molecules of therapeutic interest as potential alternative to dopamine agonists. These novel aspects of prolactin biology will be presented and discussed, with major emphasis on experimental models aimed at deciphering the mechanisms of action of autocrine/paracrine prolactin on prostate tumorigenesis.