Effect of corticosterone administration on mammary gland development and p27 expression and their relationship to the effects of energy restriction on mammary carcinogenesis

The inhibitory activity against mammary carcinogenesis mediated by energy r estriction is accompanied by a reduction in the degree of mammary ductal br anching, and an increase in adrenal cortical activity. Levels of p27/kip1 p rotein, a gene product associated with cell cycle growth arrest, have also been shown to be elevated in mammary epithelium and in mammary lesions of e nergy-restricted animals. Based on these data we have proposed that increas ed secretion of adrenal cortical steroids accounts, in part, for the effect s of energy restriction. In this experiment the hypothesis tested was that corticosterone administration would mimic the effects of energy restriction , both on mammary gland development and on levels of p27 protein in mammary ductal epithelium. To test this hypothesis corticosterone was fed to femal e rats for 4 weeks. Dietary corticosterone increased serum and urinary cort icosterone levels in a dose-dependent manner (P < 0.01). The effects of cor ticosterone treatment on mammary gland development were analyzed digitally; p27 protein was detected immunohistochemically. The ductal extension and b ranching of the mammary gland were reduced in a dose-dependent manner by co rticosterone treatment (P < 0.05); however, the magnitude of the effect was greater on ductal branching. Overall, increasing dietary corticosterone re duced the total volume of mammary epithelium in a dose-dependent manner, an effect that remained even after adjustments for differences among animals in body mass. Consistent with this effect, the amount of p27 protein presen t in ductal mammary epithelial cells increased dose-dependently in response to increasing corticosterone administration (P < 0.01). The hypothesis is proposed that dietary administration of corticosterone may imitate the effe cts of energy restriction on mammary carcinogenesis by regulation of mammar y tissue size homeostasis via p27/kip1 mediated arrest of cell cycle progre ssion.