Increased secretion of adrenal cortical
steroids may account in part for its
cancer inhibitory activity of energy restriction (ER). To test this hypothesis, a study was conducted to determine the effects of dietary administration of
corticosterone on the post-initiation stage of mammary
carcinogenesis. Eighty-four female Sprague-Dawley rats were injected with 50 mg 1-methyl-1-nitrosourea/kg body wt (i.p.) at 21 days of age. One week later, animals were randomly divided into three groups and fed control diet, or that diet to which was added 200 or 400 mg
corticosterone/kg. Diets were fed for 5 weeks after which the experiment was terminated. With increasing dietary
corticosterone, a dose-dependent reduction in the incidence (P=0.03), multiplicity (P=0.003) and size (P<0.003) of mammary
carcinomas was observed. Dietary administration of
corticosterone also reduced plasma
insulin-like growth factor-1 (IGF-1) and levels of
IGF-1 receptor in mammary
carcinomas (P<0.01). In order to investigate molecular mechanisms underlying anticancer activity, the levels and activities of cell cycle components involved in the G1-S transition were investigated in mammary
carcinomas that emerged in treated animals. Levels of
cyclin D1,
cyclin E,
cyclin-dependent kinase (CDK)-2 and CDK-4 were reduced in
carcinomas from
corticosterone treated rats; whereas, levels of
cyclin-dependent kinase inhibitors (CKI) Kip1/p27 and Cip1/p21 were elevated. Binding of these CKIs to both the
cyclin D1-CDK-4 complex and the
cyclin E-CDK-2 complex were increased and the
kinase activities of these complexes were reduced with increasing dietary
corticosterone. These effects were consistent with those observed in response to ER in vivo and
corticosterone exposure in vitro. Whereas the effects of exogenously administered
corticosterone and ER had many similarities, the lower efficacy of
corticosterone versus ER in inhibiting the carcinogenic process imply that changes in cortical
steroid metabolism alone are unlikely to explain the
cancer inhibitory activity of ER.