The Impact of Obesity on Breast Cancer

The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances—such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.     

Obesity and Cancer—Opportunities to Break the Link

Obesity is a major global health problem with a rising worldwide burden. In addition to its association with several diseases, obesity is associated with increased incidence and worse prognosis for many malignances. Many possible mechanisms that contribute to the obesity-cancer link have been proposed, but key pathways likely include steroid hormone signaling, altered gut microbiota, insulin and insulin growth factor interactions, levels of circulating adipokines, and local and systemic inflammation. By understanding these mechanisms and their interactions, we may be able to intervene to improve the public health burden imposed by obesity. Equally critical to the development of targeted intervention strategies is the identification of accurate biomarkers to better detect populations that are more or less likely to benefit from specific interventions.     

Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation

Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-I, growth hormone, vascular endothelial growth factor, and proinflammatory Th2 cytokines, such as interleukin (IL)-1beta, IL-4, and IL-6, were elevated in A-ZIP/F-1 mice. Additionally, we examined multiple phosphorylated proteins (i.e., protein kinase B/Akt and ErbB2/HER-2 kinase) associated with cancer development. Results show that many of these phosphorylated proteins were activated specifically in the A-ZIP/F-1 skin but not in the wild-type skin. These findings suggest that adipokines are not required for the promotion of tumor development and thus contradict the epidemiologic data linking obesity to carcinogenesis. We postulate that insulin resistance and inflammation are responsible for the positive correlation with cancer observed in A-ZIP/F-1 mice.     

Diet-induced obesity increases melanoma progression: involvement of Cav-1 and FASN

Recent population-based epidemiological studies strongly hint towards a link between obesity and its occurrence as well as progression of several cancers including melanoma. Although effects of obesity on breast, colon and liver cancers have been extensively investigated, the links between obesity and melanoma remain largely unexplored. Present study aimed to understand the effect of high fat diet-induced weight gain on susceptibility of C57BL/6J mice to melanoma. For this, mice routinely were fed on high fat diet for 6 months (HFD mice). Subsequently, mouse melanoma cells were injected subcutaneously in control as well as HFD mice and followed for tumor initiation and progression. We provide strong evidence that diet-induced obesity leads to increased melanoma progression in male C57BL/6J mice. We observed that increased melanoma progression is associated with enhanced Cav-1 and FASN expression in tumors from HFD mice. Cav-1 and FASN are co-ordinately regulated and Cav-1 interacts with FASN in melanoma cells. Enhanced levels of Cav-1, FASN and pAkt control melanoma cell proliferation. Our study establishes a causative relationship between diet-induced obesity and melanoma progression as well as demonstrates that obesity affects important tumorigenic pathways in melanoma.     

Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting

Background

Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure.

Main body

Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression.

Conclusions

Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC.

     

Adipokines linking obesity with colorectal cancer risk in postmenopausal women

Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.     

Adipokine regulation of colon cancer: Adiponectin attenuates interleukin‐6‐induced colon carcinoma cell proliferation via STAT‐3

Obesity results in increased circulating levels of specific adipokines, which are associated with colon cancer risk. The disease state is associated with increased leptin, insulin, IGF‐1, and IL‐6. Conversely, adiponectin levels are decreased in obese individuals. Previously, we demonstrated adipokine‐enhanced cell proliferation in preneoplastic, but not normal, colon epithelial cells, demonstrating a differential effect of adipokines on colon cancer progression in vitro. Using a model of late stage carcinoma cancer cell, namely murine MC‐38 colon carcinoma cells, we compared the effect of obesity‐associated adipokines (leptin, insulin, IGF‐1, and IL‐6) on MC‐38 cell proliferation and determined whether adiponectin (full length or globular) could modulate adipokine‐induced cell proliferation. We show that insulin and IL‐6, but not leptin and IGF‐1, induce proliferation in MC‐38 cells. Adiponectin treatment of MC‐38 cells did not inhibit insulin‐induced cell proliferation but did inhibit IL‐6‐induced cell proliferation by decreasing STAT‐3 phosphorylation and activation. Nitric oxide (NO) production was increased in MC‐38 cells treated with IL‐6; co‐treatment with adiponectin blocked IL‐6‐induced iNOS and subsequent NO production. These data are compared to previously reported findings from our laboratory using the YAMC (model normal colon epithelial cells) and IMCE (model preneoplastic) cells. The cell lines are utilized to construct a model summarizing the hormonal consequences of obesity and the impact on the differential regulation of colon epithelial cells along the continuum to carcinoma. These data, taken together, highlight mechanisms involved in obesity‐associated cancers and may lead to potential‐targeted therapies. © 2010 Wiley‐Liss, Inc.     

Obesity, adipokines, and prostate cancer (review)

Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin.     

Elevated circulating adiponectin and elevated insulin sensitivity in adiponectin transgenic mice are not associated with reduced susceptibility to colon carcinogenesis

Obesity, particularly visceral adiposity, is an established risk factor for colorectal cancer (CRC) and this is thought to result, at least in part, from insulin resistance and chronic hyperinsulinemia that may be mediated by adipokines. Serum levels of adiponectin, the most abundant protein secreted from adipocytes, are decreased in obesity and are inversely associated with insulin resistance and hyperinsulinemia. The objective of this study was to determine whether elevated circulating adiponectin plays a role in colon carcinogenesis using adiponectin transgenic (AdTg) mice that have 2–3‐fold elevated circulating adiponectin but similar body weights as wildtype (WT) littermates used as controls. Eight‐week old male and female AdTg and WT mice were treated with 4 weekly injections of the colon‐specific carcinogen azoxymethane (AOM). One week following the last dose of AOM, all mice were placed on a high‐fat diet and killed 24 weeks later, at 36 weeks of age, for the analysis of colon tumors. Glucose tolerance tests (GTT) were performed by injecting 2g/kg dextrose or 1.25–1.5 g/kg dextrose into all 12‐week and 32–35‐week‐old mice respectively, and measuring blood from the tail vein 15, 30, 60 and 120 min following glucose administration. There were no significant differences in colon tumor incidence, number or size between AdTg and WT mice of either sex. AdTg mice of both sexes displayed resistance to diet‐induced decreases in insulin sensitivity. Our results show that constitutively elevated levels of circulating adiponectin in AdTg mice do not confer protection against the development of colon tumors. © 2008 Wiley‐Liss, Inc.     

The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by RAD001

The prevalence of obesity, an established risk and progression factor for postmenopausal breast cancer, remains high in US women. Activation of Akt/mammalian target of rapamycin (mTOR) signaling plays a key role in the obesity–breast cancer link. However, the impact of weight normalization in obese postmenopausal women on breast tumorigenesis and/or Akt/mTOR activation is poorly characterized. To model this, ovariectomized female C57BL/6 mice were fed a control diet (n = 20), a calorie restriction (CR) regimen (n = 20), or a diet‐induced obesity (DIO) diet (n = 30). At week 17, DIO mice were switched to control diet, resulting in formerly obese (FOb) mice with weights identical to the controls by week 20. MMTV‐Wnt‐1 mammary tumor cells were injected at 20 wk into each mouse. Two weeks post‐injection, vehicle or the mTOR inhibitor RAD001 at 10 or 15 mg/kg body weight (n = 10/diet group) was administered by gavage twice/week until termination. Relative to controls, CR mice had decreased (and DIO mice had increased) serum insulin‐like growth factor‐1 (IGF‐1) and phosphorylation of Akt/mTOR pathway components. RAD001 decreased tumor growth in the CR, control, and FOb mice. Wnt‐1 tumor cells treated in vitro with serum from mice from each group established that diet‐dependent circulating factors contribute to tumor growth and invasiveness. These findings suggest weight normalization in obese mice does not immediately reverse tumor progression or Akt/mTOR activation. Treatment with RAD001 blocked mammary tumor development and mTOR activation observed in the FOb mice, suggesting combination of lifestyle and pharmacologic strategies may be effective for breaking the obesity–breast cancer link. © 2012 Wiley Periodicals, Inc.     

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease.     

Energy balance modulates colon tumor growth: Interactive roles of insulin and estrogen

Obesity increases colorectal cancer (CRC) risk and progression. However, the impact of obesity on CRC in women is dependent on ovarian hormone status. The purpose of this study was to determine the interactive roles of obesity and ovarian hormones on serum markers of inflammation, cell signaling, and transplanted colon tumor growth. Female C57BL/6 mice (6 wk) were either ovariectomized (OVX) or ovaries left intact (nonovariectomized, NOVX) and randomized to receive a (1) control, (2) 30% calorie‐restricted (CR), or (3) diet‐induced obese (DIO) diet regimen for 20 wk to induce differing levels of adiposity. Serum was collected and inflammatory and metabolic markers were measured using an antibody array (62 proteins) and ELISAs. Mice were subcutaneously injected with syngeneic MC38 colon cancer cells after 20 wk and sacrificed 4 wk later. CR mice had the smallest tumors irrespective of hormone status, whereas the largest tumors were observed in DIO‐OVX mice. Glucose tolerance was impaired in OVX mice, being most severe in the DIO‐OVX group. Cytokine arrays suggested that in CR animals, inhibition of tumor growth paralleled insulin sensitivity and associated changes in leptin, adiponectin, and IGF‐BPs. Conversely, in DIO‐OVX animals, tumor growth was associated with insulin and leptin resistance as well as higher levels of pro‐inflammatory proteins. In vitro, leptin and adiponectin had no effect, whereas insulin induced MC38 cell proliferation and MAPK activation. Co‐treatment with estrogen blocked the stimulatory effects of insulin. Thus, our in vitro and in vivo data indicate female reproductive hormones have a modulating effect on obesity‐induced insulin resistance and inflammation, which may directly or indirectly influence CRC progression. ©2010 Wiley‐Liss, Inc.     

Calories,carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation

Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R’s of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K–Akt–mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K–Akt–mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.     

Insulin and cancer

Obesity has recently been linked to mortality from the majority of cancers. The insulin/insulin-like growth factor (IGF) system may partly explain this effect. The metabolic syndrome, associated with hyperinsulinemia, may modulate this effect. Recent evidence supports the role of insulin and IGF-1 as important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation. In addition, the metabolic syndrome associated with a chronic inflammatory state and accompanying cytokine abnormalities may also contribute to tumor progression. Growing links between insulin and the etiology as well as prognosis in colon, prostate, pancreatic, and, particularly, breast cancer are reviewed. Of particular concern is the evidence that elevated IGF-1 may interfere with cancer therapy, adversely affecting prognosis. The role of insulin is of concern because of the increasing levels of obesity and the associated metabolic syndrome. Weight gain, through typical Western diet; limited levels of activity; and, more recently, stress-related changes in neuroendocrine function may lead to insulin resistance and hyperinsulinemia. The opportunity for a multidisciplinary approach involving nutrition, exercise, and stress reduction in an integrative setting may be crucial to limiting the insulin-resistant state and improving cancer outcomes.     

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.     

Estrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancer

Obesity is associated with the increased incidence of colon cancer. Many cancer risk factors have been identified including increased blood levels of insulin, leptin, interleukin-6, interleukin-17, tumor necrosis factor-alpha, and decreased blood levels of adiponectin. However, the role of blood levels of estrogen in obesity-associated colon cancer is controversial. Evidence showed that obesity affected men more strongly than women in the carcinogenesis of colon cancer, indicating protective effect of estrogen which is increased in obesity. However, an epidemiological study has also shown that endogenous estradiol level is an independent risk factor for colon cancer, positively associated with colon cancer after normalizing insulin, IGF-1. The controversial opinions may be caused by different effects of ER-alpha and ER-beta. ER-alpha can increase colon cancer cell proliferation and increase cancer incidence. ER-beta has the opposite effect to ER-alpha, and it causes apoptosis of colon cancer cells. The normal colonocytes mainly express ER-beta. Therefore, increased estrogen in obesity may have protective effect via ER-beta in obesity-associated colon cancer. However, with the development of colon cancer, ER-alpha is increased and ER-beta is decreased. In the late stage of colon cancer, estrogen may promote cancer development via ER-alpha. The different effects and expression of ER-alpha and ER-beta may explain the different results observed in several epidemiological studies as well as several animal experiments. Therefore, manipulation of estrogen-caused signal pathways to inhibit ER-alpha and stimulate ER-beta may have preventive and therapeutic effect for obesity-associated colon cancer.     

Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression

Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum‐induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three‐dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase‐3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor‐treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity‐prostate cancer progression link.     

Hormonal changes following tumor transplantation: factors increasing corticosterone and the relationship of corticosterone to tumor-induced anti-inflammation

EL-4 lymphoma cells transplanted to syngeneic C57BL/6J mice induced a biphasic decrease in inflammation and a bi-phasic increase in serum levels of corticosterone. In addition, this tumor altered serum levels of 3 other hormones, resulting in a biphasic decrease in insulin, an early decrease in prolactin, and a terminal severe deficiency in thyroxine. Early changes occurred 16 to 48 hr after tumor transplantation and were of variable duration, while late-phase defects developed during the last few days of life. Soluble factors associated with tumor growth may mediate certain hormonal changes since serum levels of corticosterone increased and insulin decreased following injection of tumorous ascites into normal mice. Further, injection of cell-free tumor culture supernatants increased corticosterone levels. Hormonal changes following injection of soluble factors occurred after a delay of 16 hr indicating that the factors acted indirectly. Surgical adrenalectomy blocked the corticosterone increase induced by tumor transplantation or ascites injection and eliminated the anti-inflammatory effect of tumor transplantation while significantly decreasing the effect associated with injection of tumorous ascites. Thus, the physiologically induced increase in serum levels of corticosterone reached anti-inflammatory levels. Further, elevated levels of corticosterone are a major contributing factor to anti-inflammation induced by tumorous ascites injection and constitute the principal mechanism of anti-inflammation following tumor transplantation.