Development of a mouse model of mammary gland versus uterus tissue selectivity using estrogen- and progesterone-regulated gene markers

We have identified mRNA markers of estradiol and progesterone action in the mouse mammary gland and uterus to establish an in vivo model for the evaluation of novel and potentially tissue selective estrogens and progestins. Gene chip analysis of mRNA from ovariectomized (OVX) mice treated with vehicle (V), 17β-estradiol (E2), progesterone (P) or E2 + P for 7 days identified defensinβ1 (Defβ1) and indoleamine-pyrrole 2,3 dioxygenase (INDO) as markers of E2 and P action in the mammary gland, and serine protease inhibitor, Kazal type 3 (Spink3) and G protein-coupled receptor 105 (GPR105) as markers in the uterus. Defβ1 and Spink3 are both upregulated by E2 + P, whereas INDO and GPR105 have a complementary profile of upregulation by E2 alone and suppression of the E2 effect by P. Quantitative RT-PCR analysis of mammary gland markers was concordant with histological changes. Using this model, medroxyprogesterone acetate (MPA) and tanaproget (TNPR), a novel nonsteroidal progesterone receptor agonist, were evaluated and found to have no marked tissue selectivity relative to progesterone. In addition, the ERα selective ligand propyl pyrazole triol (PPT) and the ERβ selective ligands ERB-041 and WAY-202196 were evaluated on the mammary gland endpoints of histology and Defβ1 mRNA expression, and showed that ERα stimulation is necessary and sufficient for eliciting estradiol-mediated changes in the mammary gland.