Progestins specifically suppress α-lactalbumin synthesis and secretion

Abstract

Mammary gland explants from pregnant (day 12–15) rats were cultured with insulin and prolactin, and their content and secretion of α-lactalbumin determined after exposure to a wide range of doses (0.01–300 nM) of the specific synthetic progestin (ORG2058), alone or with a maximally stimulatory dose of the highly specific glucocorticoid RU26988. ORG2058 alone suppressed α-lactalbumin synthesis below baseline, with a half-maximal effect at a concentration of <0.1 nM; RU26988-stimulated secretion was similarly abrogated by ORG2058, similarly with a half maximally effective dose of <0.1 nM. We interpret these data as suggesting that (i) given the specificity and doses of the steroids used the effect of progestins on α lactalbumin synthesis is directly via progesterone receptor occupancy, and not by competing with glucocorticoids for glucocorticoid receptors and (ii) given the shift to the left in the α-lactalbumin response (half maximal <0.1nM ORG2058) compared with receptor binding ( K d (37°C) > 1 nM), one possible model for such sensitivity is that of multiple, independent regulatory elements on the chromatin controlling α-lactalbumin gene expression, occupancy of any one of which by an activated progesterone receptor is sufficient to abrogate transcription.