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 restriction is accompanied by a reduction in the degree of mammary ductal branching, and an increase in adrenal cortical activity. Levels of p27/kip1 protein, a gene product associated with cell cycle growth arrest, have also been shown to be elevated in mammary epithelium and in mammary lesions of energy-restricted animals. Based on these data we have proposed that increased secretion of adrenal cortical steroids accounts, in part, for the effects 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 female rats for 4 weeks. Dietary corticosterone increased serum and urinary corticosterone levels in a dose-dependent manner (P < 0.01). The effects of corticosterone treatment on mammary gland development were analyzed digitally; p27 protein was detected immunohistochemically. The ductal extension and branching of the mammary gland were reduced in a dose-dependent manner by corticosterone treatment (P < 0.05); however, the magnitude of the effect was greater on ductal branching. Overall, increasing dietary corticosterone reduced 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 present 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 effects of energy restriction on mammary carcinogenesis by regulation of mammary tissue size homeostasis via p27/kip1 mediated arrest of cell cycle progression.
Zhu
Z
Z
Center for Cancer Causation and Prevention, AMC Cancer Research Center, Lakewood, CO 80214, USA.
Jiang
W
W
Thompson
H J
HJ
D000305:Adrenal Cortex Hormones / Q000097:blood / Q000502:physiology / Q000652:urine; D000311:Adrenal Glands / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D003345:Corticosterone / Q000494:pharmacology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004032:Diet; D002149:Energy Intake; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins
D000305:Adrenal Cortex Hormones; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003345:Corticosterone