Breast cancer and prostate hyperplasia are two very common diseases in humans, influenced by several different hormones, including sex hormones. The pituitary hormones growth hormone (GH) and prolactin (PRL) have also been demonstrated to have stimulatory effects on breast and prostate cells. It has even been speculated that GH and PRL might be important for the development of breast cancer and prostate hyperplasia in humans. Human-GH (hGH) can activate both GH-receptors (GHR) and PRL-receptors (PRLR) in humans and rodents. GHR and PRLR have been demonstrated in the mammary gland and prostate in several species, including humans. In order to study the potential role of GHR and PRLR stimulation in mammary tumor formation and prostate hyperplasia transgenic mice were used. Receptor specificity was investigated by using GHs and PRL from different species having specific binding to the GHR or the PRLR. Stimulation of both the GHR and the PRLR in hGH transgenic mice resulted in development of mammary adenocarcinomas at 7-9 months of age. To study the importance of selective GHR activation for tumor formation, bovine-GH (bGH) transgenic mice were used. No mammary tumors were observed in bGH transgenic mice displaying elevated levels of bGH and elevated insulin-like growth factor I (IGF-I). Rat-PRL (rPRL) transgenic mice were generated with the aim to selectively activate the PRLR. All of the rPRL transgenic female animals from two separate lines, displaying normal IGF-I levels, developed mammary adenocarcinomas at an age of 11-15 months. One of the lines had rPRL levels 4 times higher than normal peak values and the other levels in the normal range of endogenous PRL. Cell lines established from a tumor from a transgenic mouse expressing low serum levels of PRL produced rPRL and expressed PRLR. Furthermore, in organ culture experiments, an auto/paracrine function of rPRL produced from the transgene was demonstrated.Male rPRL transgenic mice developed prostate hyperplasia at an age of 10-15 months. The prostate weights were increased approximately 20 times and the DNA content 4-5 times compared with controls. Histologically, the prostate glands in the transgenic mice were distended from secretion and the amount of interstitial tissue was increased. The levels of testosterone and IGF-I were increased in the PRL transgenic animals. In bGH transgenic mice, displaying elevated IGF-I levels, the prostate gland was only slightly larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through elevated plasma IGF-I levels. In summery, activation of the PRLR but not the GHR is important for induction of mammary tumors in female mice. Rat-PRL produced locally in the mammary gland from rPRL transgenic mice could stimulate mammary differentiation in a paracrine way in vitro, suggesting that locally produced PRL might be of importance for tumor development. In mice, PRL is involved in development of prostate hyperplasia, acting directly on the prostate or via increased plasma levels of testosterone
