Dose‐dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin‐like growth factor‐1

The prevalence of obesity, an established risk and progression factor for breast and many other cancer types, remains very high in the United States and throughout the world. Calorie restriction (CR), a reduced‐calorie dietary regimen typically involving a 20–40% reduction in calorie consumption, pr...

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Published in:	Cancer medicine (Malden, MA) Vol. 1; no. 2; pp. 275 - 288
Main Authors:	Nogueira, Leticia M., Lavigne, Jackie A., Chandramouli, Gadisetti V. R., Lui, Huaitian, Barrett, J. Carl, Hursting, Stephen D.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-10-2012 Blackwell Publishing Ltd
Subjects:	Animals Body composition Body weight Breast Breast cancer Caloric Restriction Cancer biology Cancer Prevention carcinogenesis Diet Disease Progression DNA damage Energy Female Gene Expression Growth factors Insulin Insulin-Like Growth Factor I - metabolism Insulin-like growth factors Kinases Liver Mammary gland Mammary Neoplasms, Animal - prevention & control Mammary Neoplasms, Animal - therapy Mammary Neoplasms, Experimental - pathology Mammary Neoplasms, Experimental - prevention & control Mammary Neoplasms, Experimental - therapy Medical research Menopause Metabolism Mice Mice, Inbred C57BL Neoplasm Transplantation Nutrient deficiency nutrition Obesity Obesity - complications Studies Transcriptome - genetics Tumors Wnt1 Protein - genetics Womens health United States > US nutrition Cancer biology cancer prevention carcinogenesis
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Summary:	The prevalence of obesity, an established risk and progression factor for breast and many other cancer types, remains very high in the United States and throughout the world. Calorie restriction (CR), a reduced‐calorie dietary regimen typically involving a 20–40% reduction in calorie consumption, prevents or reverses obesity, and inhibits mammary and other types of cancer in multiple tumor model systems. Unfortunately, the mechanisms underlying the tumor inhibitory effects of CR are poorly understood, and a better understanding of these mechanisms may lead to new intervention targets and strategies for preventing or controlling cancer. We have previously shown that the anticancer effects of CR are associated with decreased systemic levels of insulin‐like growth factor‐1 (IGF‐1), the primary source of which is liver. We have also reported that CR strongly suppresses tumor development and growth in multiple mammary cancer models. To identify CR‐responsive genes and pathways, and to further characterize the role of IGF‐1 as a mediator of the anticancer effects of CR, we assessed hepatic and mammary gland gene expression, hormone levels and growth of orthotopically transplanted mammary tumors in control and CR mice with and without exogenous IGF‐1. C57BL/6 mice were fed either control AIN‐76A diet ad libitum (AL), subjected to 20%, 30%, or 40% CR plus placebo timed‐release pellets, or subjected to 30% or 40% CR plus timed‐release pellets delivering murine IGF‐1 (mIGF‐1, 20 μg/day). Compared with AL‐fed controls, body weights were decreased 14.3% in the 20% CR group, 18.5% in the 30% CR group, and 38% in the 40% CR group; IGF‐1 infusion had no effect on body weight. Hepatic transcriptome analyses indicated that compared with 20% CR, 30% CR significantly modulated more than twice the number of genes and 40% CR more than seven times the number of genes. Many of the genes specific to the 40% CR regimen were hepatic stress‐related and/or DNA damage‐related genes. Exogenous IGF‐1 rescued the hepatic expression of several metabolic genes and pathways affected by CR. Exogenous IGF‐1 also rescued the expression of several metabolism‐ and cancer‐related genes affected by CR in the mammary gland. Furthermore, exogenous IGF‐1 partially reversed the mammary tumor inhibitory effects of 30% CR. We conclude that several genes and pathways, particularly those associated with macronutrient and steroid hormone metabolism, are associated with the anticancer effects of CR, and that reduced IGF‐1 levels can account, at least in part, for many of the effects of CR on gene expression and mammary tumor burden. We compared the effects of different levels of calorie restriction (CR), with and without infusion of IGF‐1 (a potential mediator of the anticancer effects of CR), on hepatic and mammary gland gene expression and mammary tumor progression. We found (1) several genes and pathways, particularly those associated with macronutrient and steroid hormone metabolism, are associated with the anticancer effects of moderate (30%) CR; (2) mild CR (20%) has little effect on gene expression relative to control, whereas 40% CR modulates metabolic pathways as well as a broad panel of stress‐related and DNA damage‐related genes, suggesting this level of CR is too severe; and (3) reduced IGF‐1 levels can account, at least in part, for many of the effects of CR on metabolism‐related gene expression and mammary tumor burden.
Bibliography:	Contributed equally to this manuscript. Funding Information Funding for this work was provided by a grant from the Breast Cancer Research Foundation to S. D. Hursting.
ISSN:	2045-7634 2045-7634
DOI:	10.1002/cam4.23