Journal Article

Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: <i>in vivo</i> effects of corticosterone on cell cycle machinery in mammary carcinomas

Zongjian Zhu, Weiqin Jiang and Henry J. Thompson

in Carcinogenesis

Volume 24, issue 7, pages 1225-1231
Published in print July 2003 | ISSN: 0143-3334
Published online July 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg077
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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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.

Keywords: CDK, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; Rb, retinoblastoma; ECL, enhanced chemiluminescence; ER, energy restriction; IGF, insulin growth factor; MNU, 1-methyl-1-nitrosourea

Journal Article.  4976 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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