Carcinogenesis Advance Access published online on May 9, 2003
Carcinogenesis, doi:10.1093/carcin/bgg077
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Cancer Prevention Laboratory, Colorado State University, Fort Collins, CO 80523-1173, USA
* Corresponding author. E-mail: henry.thompson{at}colostate.edu.
Received 13 December 2002
; revised 13 March 2003
; accepted 25 April 2003
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 MNU/kg body weight (i.p) at 21 days of age. One week later, animals were randomly divided into 3 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 anti-cancer 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, 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 CKI's 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. While 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.
Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas
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