NEW INSIGHTS IN THE MOLECULAR MECHANISM OF PROGESTIN-INDUCED PROLIFERATION OF MAMMARY EPITHELIUM - INDUCTION OF THE LOCAL BIOSYNTHESIS OF GROWTH-HORMONE (GH) IN THE MAMMARY-GLAND OF DOGS, CATS AND HUMANS

In contrast to the protective, anti-proliferative, action of progestin s on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epi thelium. Until now there was no final molecular explanation of this di screpancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF )-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have t he typical pulsatile secretion pattern, and are not sensitive to stimu lation with GHRH or to inhibition with somatostatin. The autonomous se cretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the can ine mammary gland where progestins induce the expression of the gene e ncoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is p redominantly located in single positive epithelial cells with an inter mediate position between luminal- and myo-epithelium. Progestin-induce d fibroadenomatous changes in the mammary gland of cats are also assoc iated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demons trated by RT-PCR. The presence of GH mRNA is associated with the prese nce of immunoreactive GH as shown by immunohistochemistry. Sequence an alysis revealed 100% homology to the pituitary expressed GH gene. In m alignant mammary tumours of humans and dogs GH expression is also foun d in specimens negative for progesterone receptors as measured by liga nd binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the actio n of progestins on proliferation of mammary epithelium. It needs, howe ver, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on t he proliferation of mammary epithelium. (C) 1996 Elsevier Science Ltd.