IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression.

Luminal breast tumors with little or no estrogen receptor α expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.

Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-κB activation, and inflammation-related gene expression.

Calorie restriction (CR) prevents obesity and has potent anticancer effects associated with altered hormones and cytokines. We tested the hypothesis that CR inhibits MC38 mouse colon tumor cell growth through modulation of hormone-stimulated nuclear factor (NF)-κB activation and protumorigenic gene expression. Female C57BL/6 mice were randomized (n = 30/group) to receive control diet or 30% CR diet. At 20 wk, 15 mice/group were killed for body composition analysis. At 21 wk, serum was obtained for hormone analysis. At 22 wk, mice were injected with MC38 cells; tumor growth was monitored for 24 d. Gene expression in excised tumors and MC38 cells was analyzed using real-time RT-PCR. In vitro MC38 NF-κB activation (by p65 ELISA and immunofluorescence) were measured in response to varying IGF-1 concentrations (1-400 ng/mL). Relative to controls, CR mice had decreased tumor volume, body weight, body fat, serum IGF-1, serum leptin, and serum insulin, and increased serum adiponectin (P < 0.05, each). Tumors from CR mice, versus controls, had downregulated inflammation- and/or cancer-related gene expression, including interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, cyclooxygenase-2, chemokine (C-C motif) ligand-2, S100A9, and F4/80, and upregulated 15-hydroxyprostaglandin dehydrogenase expression. In MC38 cells in vitro, IGF-1 increased NF-κB activation and NF-κB downstream gene expression (P < 0.05, each). We conclude that CR, in association with reduced systemic IGF-1, modulates MC38 tumor growth, NF-κB activation, and inflammation-related gene expression. Thus, IGF-1 and/or NF-κB inhibition may pharmacologically mimic the anticancer effects of CR to break the obesity-colon cancer link.

Using components of the vitamin D pathway to prevent and treat colon cancer.

The objective of this review was to analyze the components of vitamin D and their potential usefulness in preventing and treating colorectal cancer. The active form of vitamin D, 1α,25(OH(2) )D(3) , targets the wnt/ß-catenin pathway by upregulating key tumor suppressor genes such as E-cadherin, which promotes an epithelial phenotype, but this is only possible when the vitamin D receptor (VDR) is present. Colorectal cell lines have shown that VDR expression levels decrease in the later stages of colon cancer. In colorectal cancers with low VDR expression, treatments to increase VDR expression could target alterations at the genomic and epigenomic levels by modulating transcription factors such as SNAIL1 and by utilizing histone deacetyltransferase inhibitors, respectively. Finally, epidemiological studies suggest that the current US Recommended Dietary Allowance should be increased to 2,000 IU in order to raise serum 25(OH)D(3) levels above 30 ng/mL. This increase in vitamin D status can be obtained most efficiently from sun exposure or vitamin D supplementation. In summary, vitamin D and its metabolites could be utilized in strategies to treat and prevent colon cancer.

Ethanol inhibits B16-BL6 melanoma metastasis and cell phenotypes associated with metastasis.

BACKGROUND: Every year, approximately 68,000 new cases of malignant melanoma are diagnosed in the US. Ethanol consumption inhibits metastasis of melanoma in mice, but the mechanism is not well understood. MATERIALS AND METHODS: C57BL/6J ob/+ mice, given either water or 20% ethanol, were injected intravenously with B16-BL6 melanoma cells to determine pulmonary metastasis. The effects of ethanol on cell phenotypes and markers of the epithelial-to-mesenchymal transition were determined in cell culture. RESULTS: In mice, ethanol consumption inhibited experimental pulmonary metastasis. This inhibition was associated with decreased body weight, and levels of systemic leptin, and insulin. In cell culture, ethanol inhibited B16-BL6 cell motility, invasion, and anchorage-independent growth. Additionally, ethanol reduced Snai1 expression and increased E-cadherin expression. Lastly, ethanol increased the expression of Kiss1 metastasis-suppressor and the metastasis suppressor Nm23/nucleoside diphosphate kinase. CONCLUSION: In both animal and in cell culture conditions, ethanol inhibited the metastatic ability of B16-BL6 melanoma cells.

Exogenous estrogen protects mice from the consequences of obesity and alcohol.

OBJECTIVE: Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. METHODS: Ovariectomized female mice were fed diets to induce different body weights (calorie restricted, low fat, high fat), provided water or 20% alcohol, implanted with placebo or estrogen pellets and injected with Wnt-1 mouse mammary cancer cells. RESULTS: Our results show that obesity promoted the growth of Wnt-1 tumors and induced fatty liver. Tumors tended to be larger in alcohol-consuming mice and alcohol exacerbated fatty liver in obese mice. Estrogen treatment promoted weight loss in obese mice, which was associated with the suppression of tumor growth and fatty liver. CONCLUSIONS: In summary, we show that estrogen protects against obesity, which is associated with the inhibition of fatty liver and tumor growth.

Alcohol promotes mammary tumor development via the estrogen pathway in estrogen receptor alpha-negative HER2/neu mice.

BACKGROUND: Alcohol consumption is an established risk factor for breast cancer. Yet, the mechanism by which alcohol affects breast cancer development remains unresolved. The transition from the premenopausal to the postmenopausal phase is associated with a drastic reduction in systemic estrogen levels. It is not clear whether the risk of breast cancer attributable to alcohol consumption is modified by the different levels of estrogen found in pre- and postmenopausal women. The objective of this study is to determine whether the effects of alcohol on mammary tumor development are dependent on the presence of ovarian estrogen. METHODS: As a model of breast cancer, we used mouse mammary tumor virus (MMTV)-neu transgenic mice that overexpress the human epidermal growth factor receptor 2 (HER2/neu) in the mammary epithelium, resulting in the development of estrogen receptor alpha (ERα)-negative mammary tumors. The mammary tumorigenesis process in these mice is similar to that of patients with HER2 breast cancer. Nonovariectomized (NOVX) and ovariectomized (OVX) MMTV-neu mice were exposed to 0, 5, and 20% ethanol in the drinking water. Breast cancer development and progression were determined alongside the effects of alcohol on estrogen availability and signaling. RESULTS: Our data show that 20% alcohol consumption promoted tumor development in MMTV-neu mice only in the presence of ovarian hormones. Tumor promotion was associated with increased systemic estrogen levels, increased expression of aromatase (the rate-limiting enzyme in estrogen synthesis), and increased expression of ERα in the tumors of 20% alcohol-consuming MMTV-neu mice. Additionally, we show that ovariectomy (removal of the ovaries and ovarian hormone production) blocked the effects of 20% alcohol on tumor development. CONCLUSIONS: Our results support the notion that alcohol consumption promotes HER2 breast cancer development via the estrogen signaling pathway. Additionally, they suggest that the effects of alcohol on breast cancer may be prevented by blocking estrogen signaling.

Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance.

PURPOSE: Obesity increases the risk of diabetes. The dysregulation of estrogen metabolism has been associated with the susceptibility to obesity and diabetes. Here, we explore the role estrogen plays in sex differences in obesity and glucose metabolism, specifically adipocyte biology. METHODS: We randomized C57BL/6 J male, non-ovariectomized female, ovariectomized female, and ovariectomized female mice supplemented with 17ß estradiol to receive a calorie-restricted, low- or a high-fat diet (15 mice per group). We measured weight gained, calories consumed, percent body fat, abdominal adipose tissue, adipocyte size, lipogenic and adipogenic gene expression, and glucose tolerance. RESULTS: Male mice had a higher susceptibility to obesity than intact female mice. However, removal of the ovaries in female mice eliminated the protection to obesity and estrogen supplementation restored this protection. Male and ovariectomized female mice gained weight predominately in the form of abdominal adipose tissue possibly due to an increase in adipocyte size. Moreover, for mice consuming the high-fat diet, male and ovariectomized female mice had significantly higher levels of leptin mRNA and lower hormone-sensitive lipase mRNA relative to intact female mice and ovariectomized female mice supplemented with estrogen. Additionally, estrogen had a strong inhibitory effect on key adipogenic genes in non-ovariectomized female and ovx-female mice supplemented with estrogen. Finally, we show that male and ovariectomized female mice consuming the high-fat diet had a higher incidence of glucose intolerance. CONCLUSION: Estrogen protects female mice from obesity and impaired glucose tolerance possibly by modulating the expression of genes regulating adipogenesis, lipogenesis, and lipolysis.

Adipocytes Promote B16BL6 Melanoma Cell Invasion and the Epithelial-to-Mesenchymal Transition.

Metastatic melanoma is one of the most deadly and evasive types of cancer. On average, cancer patients with metastatic melanoma survive only 6-9 months after diagnosis. Epidemiological and animal studies suggest that obesity increases the metastatic ability of malignant melanoma, though the mechanism is not known. In the present studies, we assessed the ability of 3T3L1 adipocytes to modulate B16BL6 melanoma cell invasion and the Epithelial-to-Mesenchymal Transition (EMT). For this purpose, we induced the differentiation of 3T3L1 fibroblasts to adipocytes. Then, we collected the cell culture media from both fibroblasts and adipocytes and determined their effect on the invasive ability and EMT gene expression of B16BL6 melanoma cells. Results show that adipocyte media increased that ability of B16BL6 cells to invade. The higher invasive ability of B16BL6 melanoma cells was associated with increased expression of EMT genes such as Snai1, MMP9, Twist, and Vimentin. Additionally, the expression of the cell-to-cell adhesion protein E-cadherin and the metastasis suppressor gene Kiss1 were down-regulated in these B16BL6 cells. Also, adipocytes had high levels of the pro-inflammatory cytokine Interleukin 6 (IL-6). Treatment of B16BL6 cells with IL-6 elicited similar effects as the adipocyte media; IL-6 promoted the invasive ability of B16BL6 melanoma cells, increased the expression of Snai1, and decreased Kiss1 expression. IL-6 neutralization, however, did not have a visible effect on adipocyte media-induced invasion and snai1 staining. In summary, adipocytes may increase the invasive ability of B16BL6 melanoma cells by promoting EMT and decreasing the expression of genes such as E-cadherin and Kiss1.

Ob/ob serum promotes a mesenchymal cell phenotype in B16BL6 melanoma cells.

In 2009, malignant melanoma was responsible for approximately 9,000 deaths in the US. These deaths are often associated with aggressive metastasis to secondary sites such as the lungs. Epidemiological and animal studies suggest that obesity is a risk factor for melanoma. Others have shown that B16BL6 melanoma cells metastasize more aggressively in obese ob/ob than in lean mice. However, the mechanism by which obesity promotes B16BL6 melanoma metastasis in ob/ob mice has not been identified. In the present study, we used serum obtained from control and ob/ob leptin-deficient obese mice to determine if obese serum increases the aggressive phenotype of melanoma cells. Results showed that ob/ob serum has higher levels of resistin, insulin, tPAI1, IL-6, TNF-α, and MCP-1 compared to control serum. We showed that ob/ob serum increases the invasive ability of B16BL6 melanomas. To further determine the mechanism by which ob/ob serum increases the invasive ability of melanomas, we determined the effect of ob/ob and control serum on genes associated with the epithelial-to-mesenchymal transition (EMT). Cancer cells with a mesenchymal phenotype have a higher metastatic ability. Snai1 and Twist are genes that are strongly associated with EMT and metastasis of melanomas. Our results showed that ob/ob serum increases the expression of Snai1 and Twist. Moreover, ob/ob serum increased matrix metalloproteast 9 (MMP9) activity and decreased the expression of E-cadherin and the metastasis suppressor gene Kiss1. In summary, results suggest that obesity may increase the metastatic ability of melanoma by promoting a mesenchymal cell phenotype.

Estrogen inhibits the effects of obesity and alcohol on mammary tumors and fatty liver.

The risk of developing breast cancer and fatty liver is increased by alcohol consumption. The objective of the present study was to determine if obesity and exogenous estrogen supplementation alter the effects of alcohol on mammary tumorigenesis and fatty liver. Ovariectomized female mice were (1) fed diets to induce overweight and obese phenotypes, (2) provided water or 20% alcohol, (3) implanted with placebo, low- or high-dose estrogen pellets and (4) injected with Met-1 mouse mammary cancer cells. Alcohol-consuming mice were more insulin sensitive and developed larger tumors than water consuming mice. Obese mice developed slightly larger tumors than control mice. Alcohol consumption and obesity increased growth factors, hepatic steatosis, activation of Akt, and inhibited the caspase-3 cascade. Estrogen treatment triggered the loss of body fat, induced insulin sensitivity, suppressed tumor growth, reduced growth factors and improved hepatic steatosis. Results show that the effects of alcohol on mammary tumor and fatty liver are modified by obesity and estrogen supplementation.

Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway.

BACKGROUND: Alcohol consumption is an established risk factor for breast cancer metastasis. Yet, the mechanism by which alcohol promotes breast cancer metastases is unknown. The ability of cancer cells to invade through tissue barriers (such as basement membrane and interstitial stroma) is an essential step towards establishing cancer metastasis. In the present study, we identify and examine the roles of two genes, Nm23 and ITGA5, in alcohol-induced breast cancer cell invasion. METHODS: Human breast cancer T47D cells were treated with ethanol at various concentrations. Boyden chamber invasion assays were used to measure cellular invasive ability. The mRNA expression level of metastasis suppressor genes including Nm23 was determined by qRT-PCR. ITGA5 was identified using a qRT-PCR array of 84 genes important for cell-cell and cell-extracellular matrix interactions. Nm23 overexpression in addition to Nm23- and ITGA5 knock-down were used to determine the role of the Nm23-ITGA5 pathway on cellular invasive ability of T47D cells. Protein expression levels were verified by Western blot. RESULTS: Alcohol increased the invasive ability of human breast cancer T47D cells in a dose-dependent manner through the suppression of the Nm23 metastatic suppressor gene. In turn, Nm23 down-regulation increased expression of fibronectin receptor subunit ITGA5, which subsequently led to increased cellular invasion. Moreover, Nm23 overexpression was effective in suppressing the effects of alcohol on cell invasion. In addition, we show that the effects of alcohol on invasion were also inhibited by knock-down of ITGA5. CONCLUSIONS: Our results suggest that the Nm23-ITGA5 pathway plays a critical role in alcohol-induced breast cancer cell invasion. Thus, regulation of this pathway may potentially be used to prevent the establishment of alcohol-promoted metastases in human breast cancers.

Alcohol consumption promotes mammary tumor growth and insulin sensitivity.

Epidemiological data show that in women, alcohol has a beneficial effect by increasing insulin sensitivity but also a deleterious effect by increasing breast cancer risk. These effects have not been shown concurrently in an animal model of breast cancer. Our objective is to identify a mouse model of breast cancer whereby alcohol increases insulin sensitivity and promotes mammary tumorigenesis. Our results from the glucose tolerance test and the homeostasis model assessment show that alcohol consumption improved insulin sensitivity. However, alcohol-consuming mice developed larger mammary tumors and developed them earlier than water-consuming mice. In vitro results showed that alcohol exposure increased the invasiveness of breast cancer cells in a dose-dependent manner. Thus, this animal model, an in vitro model of breast cancer, may be used to elucidate the mechanism(s) by which alcohol affects breast cancer.

Effects of body weight and alcohol consumption on insulin sensitivity.

BACKGROUND: Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways. METHOD: Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes. RESULTS: Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1alpha; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9). CONCLUSION: We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.

Alcohol consumption, obesity, estrogen treatment and breast cancer.

Alcohol consumption increases breast cancer risk in postmenopausal women in a dose-dependent manner. The objective of the present study was to determine if the effect of alcohol on mammary cancer is modified by body weight and exogenous estrogen. Ovariectomized mice of various body weights, receiving estrogen or placebo supplementation, and consuming water or alcohol were injected with mammary cancer cells. Alcohol intake resulted in insulin sensitivity and increased tumor growth in obese mice. Exogenous estrogen alone inhibited tumor growth. The combination of estrogen and alcohol overcame the inhibitory effects of estrogen on tumor growth in obese mice. Alcohol consumption increased the circulating estrogen and leptin levels. In conclusion, alcohol and estrogen treatment can modify mammary tumor growth, possibly through the regulation of estrogen and leptin, especially in obese mice.

Obesity impairs wound healing in ovariectomized female mice.

Obesity is increasing worldwide. Estrogen protects female mice from gaining weight in contrast to ovariectomy. Excess weight can inhibit wound healing. We determine the effects of obesity on wound healing in the presence and absence of estrogen. For this purpose, we generated (ovariectomized (OVX) and non-ovariectomized (NOVX)) lean mice by feeding a 30% calorie-restricted diet (CR), overweight mice a low-fat (LF) diet and obese mice a high-fat (HF) diet. CR mice had the lowest, LF an intermediate, and HF mice the highest body weights. OVX exacerbated weight gain in female mice. Wounds healed fastest in CR mice regardless of estrogen status. Contrastingly, wound healing in OVX obese female mice was delayed. In sum, OVX increased the propensity of gaining weight, CR mice healed wounds more rapidly than obese mice irrespective of estrogen status, and obesity in the absence of estrogen impaired wound healing.

Dietary calcium source influences body composition, glucose metabolism and hormone levels in a mouse model of postmenopausal obesity.

BACKGROUND: The prevalence of obesity has risen dramatically, with postmenopausal women particularly prone to increased adiposity. Epidemiologic data suggest that dietary calcium, particularly from dairy products, can decrease weight gain. The aim of this study was to evaluate effects of different calcium sources in a mouse model of postmenopausal obesity. MATERIALS AND METHODS: Ovariectomized C57BL/6 mice were randomized to either low-fat (LF) or high-fat (HF) diets containing either calcium phosphate from non-fat dried milk and whey mineral concentrate (dairy) or calcium carbonate (supplement). RESULTS: Dairy, but not supplement, decreased weight gain and percent body fat in HF mice, with no effect on food consumption. Dairy improved insulin resistance and glucose tolerance, while supplement increased bone mineral density in LF mice. Dairy had no effect on bone. CONCLUSION: The beneficial effects of dietary calcium on body weight and bone health after menopause may be significantly influenced by other dietary components.

Obesity provides a permissive milieu in inflammation-associated carcinogenesis: analysis of insulin and IGF pathways.

Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. However, recent studies in fatless A-Zip/F-1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other molecules frequently associated with obesity and carcinogenesis: insulin, insulin-like growth factor-1, and inflammatory cytokines. Therefore, we postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention or therapeutic targets for disrupting the obesity-cancer link.

Differential susceptibility to obesity between male, female and ovariectomized female mice.

BACKGROUND: The prevalence of obesity has increased dramatically. A direct comparison in the predisposition to obesity between males, premenopausal females, and postmenopausal females with various caloric intakes has not been made. To determine the effects of sex and ovarian hormones on the susceptibility to obesity, we conducted laboratory studies with mice. To eliminate confounders that can alter body weight gain, such as age and food consumption; we used mice with the same age and controlled the amount of calories they consumed. METHODS: We determined sex-specific susceptibility to obesity between male, non-ovariectomized female, and ovariectomized female mice. To compare susceptibility to gaining body weight between males and females, animals from each sex were exposed to either a 30% calorie-restricted, low-fat (5% fat), or high-fat (35% fat) diet regimen. To establish the role of ovarian hormones in weight gain, the ovaries were surgically removed from additional female mice, and then were exposed to the diets described above. Percent body fat and percent lean mass in the mice were determined by dual energy x-ray absorptiometry (DEXA). RESULTS: In all three diet categories, male mice had a greater propensity of gaining body weight than female mice. However, ovariectomy eliminated the protection of female mice to gaining weight; in fact, ovariectomized female mice mimicked male mice in their susceptibility to weight gain. In summary, results show that male mice are more likely to become obese than female mice and that the protection against obesity in female mice is eliminated by ovariectomy. CONCLUSION: Understanding metabolic differences between males and females may allow the discovery of better preventive and treatment strategies for diseases associated with body weight such as cancer and cardiovascular disease.

Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link.

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.

Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones.

Obesity increases incidence and mortality of breast cancer in postmenopausal women. Mechanisms underlying this association are poorly understood. Suitable animal models are needed to elucidate potential mechanisms for this association. To determine the effects of obesity on mammary tumor growth, nonovariectomized and ovariectomized C57BL/6 mice of various body weights (lean, overweight, and obese) were implanted subcutaneously with mammary tumor cells from syngeneic Wnt-1 transgenic mice. In mice, the lean phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status. Ovariectomy delayed Wnt-1 tumor growth consistent with the known hormone responsiveness of these tumors. However, obesity accelerated tumor growth in ovariectomized but not in nonovariectomized animals. Diet-induced obesity in a syngeneic mouse model of breast cancer enhanced tumor growth, specifically in the absence of ovarian hormones. These results support epidemiological evidence that obesity is associated with increased breast cancer incidence and mortality in postmenopausal but not premenopausal women. In contrast, maintaining a lean body weight phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status.