The prevalence of obesity, an established risk factor for several types of cancer, has increased steadily over the past several decades in the United States. New targets and strategies for offsetting the effect of obesity on cancer risk are urgently needed. In the present study, we examined the effect of dietary energy balance manipulation on steady-state signaling in multiple epithelial tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR) pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60 kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks. Relative to the control group, the DIO regimen increased, whereas CR decreased, circulating insulin-like growth factor-I (IGF-I) as has previously been reported. Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited, activation of Akt and mTOR, regardless of epithelial tissue or genetic background. In contrast, activation of AMP-activated protein kinase was modulated by dietary energy balance manipulation in the liver but not in the epidermis or dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR mice also revealed reduced activation of both the IGF-I receptor and epidermal growth factor receptor in CR mice, compared with control mice or mice maintained on the DIO regimen. Taken together, these novel findings suggest that dietary energy balance modulates signaling through cell-surface receptors (i.e., IGF-I receptor and epidermal growth factor receptor), affecting activation of multiple downstream pathways including Akt and mTOR, thus providing important dietary and pharmacologic targets for disrupting the obesity-cancer link.

Transgenic mice expressing human insulin-like growth factor 1 (IGF-1) in basal epithelial cells of prostate have been characterized. Transgene expression led to activation of the IGF-1 receptor and spontaneous tumorigenesis in prostate epithelium. Hyperplasia was evident in these mice by 2-3 months of age. Atypical hyperplasias and prostatic intraepithelial neoplasia were evident by 6 -7 months of age. Well differentiated adenocarcinomas appeared in mice 6 months or older. Less differentiated tumors, diagnosed as small cell carcinomas, were also observed in two of the older mice. Both lobes of the mouse prostate gland (dorsolateral and ventral) presented preneoplastic and neoplastic changes. The incidence of tumors in mice >6 months of age (38 mice total) was 50%. The development of neoplasia in these transgenic mice appeared to follow a stepwise progression through early preneoplastic changes that ultimately culminated in frank neoplasia. These mice offer an animal model for prostate cancer that will allow study of the stepwise development of this disease and the mechanism(s) whereby IGF-1 mediates this process. P rostate cancer is the most commonly diagnosed cancer in men in the United States (1). Progress in prostate disease research has been impaired by the lack of adequate animal models that reproduce the human disease. There are several established rat models of prostate cancer that are either hormonally and͞or chemically induced, such as the Lobund Wistar or Nobel rat models (2-5). In these models, the time frame to adenocarcinoma is 12-24 months. Spontaneous adenocarcinomas develop in the Dunning model (R-3327 system), which is carried as both cell lines and transplantable tumors in syngeneic Copenhagen rats (4). All of these model systems have certain limitations that have hampered their utility. Recently, several laboratories have created transgenic models in which prostate adenocarcinomas develop with high frequency (6-10). All of these models are based on expression of SV40-T antigen in prostate epithelium. Thus, a potential limitation of these models is the use of a transgene not directly involved in human prostate cancer. In some of these models, tumors develop rapidly (in some cases by 10-12 weeks), are poorly differentiated or undifferentiated, and progress rapidly to metastatic disease (6-8, 10).Recently, Chan et al. (11) reported a strong positive association between serum insulin-like growth factor 1 (IGF-1) levels and prostate cancer risk. The importance of IGF-1 receptor (IGF-1r) signaling in neoplastic transformation is clearly evident from a variety of studies (reviewed in refs. 12-16). Several transgenic models have been developed to explore the role of IGF-1r signaling in cellular growth and neoplasia (17)(18)(19)(20). However, with the exception of transgenic mice in which IGF-2 expression was driven by the major urinary protein promoter (MUP), none developed spontaneous tumors in any tissue. The MUP͞IGF-2 transgenic mice developed a variety of tumors, primarily hepatocellular carcinoma...

Aberrant activation of the phosphoinositide-3-kinase (PI3K)/ PTEN/Akt pathway, leading to increased proliferation and decreased apoptosis, has been implicated in several human pathologies including cancer. Our previous data have shown that Akt-mediated signaling is an essential mediator in the mouse skin carcinogenesis system during both the tumor promotion and progression stages. In addition, overexpression of Akt is also able to transform keratinocytes through transcriptional and posttranscriptional processes. Here, we report the consequences of the increased expression of Akt1 (wtAkt) or constitutively active Akt1 (myrAkt) in the basal layer of stratified epithelia using the bovine keratin K5 promoter. These mice display alterations in epidermal proliferation and differentiation. In addition, transgenic mice with the highest levels of Akt expression developed spontaneous epithelial tumors in multiple organs with age.

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