EVIDENCE THAT THE GROWTH-HORMONE RECEPTOR MEDIATES DIFFERENTIATION AND DEVELOPMENT OF THE MAMMARY-GLAND

We have shown that nonlactogenic rat (r) GH is far more potent than rP RL in inducing rat mammary development. To determine the relative role s of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, P RLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary developme nt was assessed histologically by counting terminal end buds and alveo lar structures in glands from sexually immature, hypophysectomized, ca strated, estradiol-treated rats. Hormones were implanted, in Elvax pel lets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with r GH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. Th ese four hormones were also found to bind to GH receptors with high af finity. In contrast, little development occurred with hPRL, rPRL, rhPL , ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH alte red to reduce binding to GH and PRL receptors. All of then substances are more than 50-fold reduced in binding to the GH receptor, yet can b ind and activate lactogenic receptors. Thus, only those natural or mut ant pituitary or placental hormones with high binding affinity to GH r eceptors induce mammary development, suggesting that GH receptors play a central role in this process.