Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, 20892 USA.
Cancer Med. 2012 Oct;1(2):275-88. doi: 10.1002/cam4.23. Epub 2012 Aug 6.
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.
肥胖是乳腺癌和许多其他癌症类型的既定风险和进展因素，其在美国和全球的流行率仍然很高。热量限制（CR）是一种低热量饮食方案，通常涉及减少 20-40%的热量摄入，它可以预防或逆转肥胖，并抑制多种肿瘤模型系统中的乳腺和其他类型的癌症。不幸的是，CR 对肿瘤抑制作用的机制尚不清楚，更好地了解这些机制可能会为预防或控制癌症提供新的干预靶点和策略。我们之前已经表明，CR 的抗癌作用与系统胰岛素样生长因子-1（IGF-1）水平降低有关，IGF-1 的主要来源是肝脏。我们还报告说，CR 强烈抑制多种乳腺肿瘤模型中的肿瘤发生和生长。为了确定 CR 反应基因和途径，并进一步表征 IGF-1 作为 CR 抗癌作用的介质，我们评估了对照和 CR 小鼠的肝和乳腺组织基因表达、激素水平以及原位移植乳腺肿瘤的生长，这些小鼠分别给予对照 AIN-76A 饮食自由（AL）、20%、30%或 40%CR 加安慰剂定时释放丸，或 30%或 40%CR 加定时释放丸输送小鼠 IGF-1（mIGF-1，20 μg/天）。与 AL 喂养的对照组相比，20%CR 组体重减轻 14.3%，30%CR 组体重减轻 18.5%，40%CR 组体重减轻 38%；IGF-1 输注对体重没有影响。肝转录组分析表明，与 20%CR 相比，30%CR 显著调节了两倍以上的基因，而 40%CR 则调节了七倍以上的基因。许多特定于 40%CR 方案的基因与肝脏应激相关和/或与 DNA 损伤相关。外源性 IGF-1 挽救了 CR 影响的几种代谢基因和途径的肝表达。外源性 IGF-1 还挽救了 CR 影响乳腺中几种代谢和癌症相关基因的表达。此外，外源性 IGF-1 部分逆转了 30%CR 对乳腺肿瘤的抑制作用。我们得出结论，有几个基因和途径，特别是与宏量营养素和类固醇激素代谢相关的基因和途径，与 CR 的抗癌作用有关，并且降低 IGF-1 水平至少可以部分解释 CR 对基因表达和乳腺肿瘤负担的许多影响。
