Insulin resistance: A significant risk factor of endometrial cancer

Gynecologic Oncology 125 (2012) 751–757

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Review

Insulin resistance: A significant risk factor of endometrial cancer Nan Mu a, 1, Yuanxi Zhu b, 1, Yingmei Wang a, Huiying Zhang a, Fengxia Xue a,⁎ a b

Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China Department of Breast Cancer Surgery, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People's Republic of China

a r t i c l e

i n f o

Article history: Received 25 October 2011 Accepted 18 March 2012 Available online 23 March 2012 Keywords: Insulin resistance Endometrial cancer Obesity PI3K/Akt Ras/MAPK Adipokine

a b s t r a c t Objective. To review the role played by insulin resistance in the development of endometrial cancer. Methods. Relevant manuscripts and studies were searched on Medline using the terms endometrial cancer, insulin resistance, obesity, adipokine, C-peptide, leptin, adiponectin, plasminogen activator inhibitor-1, insulin, PI3K/Akt, Ras/MAPK and metformin alone or in combination. Results. Epidemiological studies have shown that insulin resistance is an important potential risk factor of endometrial cancer, and several research studies have been undertaken to determine the mechanism underlying its link to this malignant disease. Risk factors of insulin resistance, such as the inflammatory mediators, adipokines adiponectin, leptin and plasminogen activator inhibitor-1 and excessive androgen are also risk factors of endometrial cancer. High levels of insulin induced by insulin resistance have been found to exert direct and indirect effects that contribute to the development of endometrial cancer. Insulin directly promotes cell proliferation and survival through the PI3K/Akt and Ras/MAPK pathways. Moreover, the network among insulin, estrogen and insulin-like growth factor-1 also contributes to the development of endometrial cancer. Indirectly, insulin leads to changes in sex hormone levels, including increases in the levels of estrogen. Additionally, a small number of studies suggested that metformin, an insulin-sensitizing agent, has therapeutic potential for endometrial cancer. Conclusions. This evidence suggests that insulin resistance plays a central role in endometrial cancer development. Understanding the relationship between insulin resistance and endometrial cancer may supply new ideas to fight this malignancy. Furthermore, combating insulin resistance may be a useful preventive and therapeutic strategy for endometrial cancer. © 2012 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiological evidence of insulin resistance as a risk factor of EC . . . . . . . . Molecular correlates of insulin resistance and EC . . . . . . . . . . . . . . . . Effects of insulin on EC development . . . . . . . . . . . . . . . . . . . . . Promising biomarkers to evaluate the relationship of insulin resistance and EC Therapies for insulin resistance and their potential applications in EC . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

⁎ Corresponding author at: Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154, Anshan Road, He Ping District, Tianjin, People's Republic of China. E-mail address: [email protected] (F. Xue). 1 These authors contributed equally to the preparation of this manuscript. 0090-8258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2012.03.032

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. In 2011, there were an estimated 46,470 new cases and 8120 deaths from EC in the United States alone [1]. Unfortunately, the etiology of this disease is not clearly understood. The most prevailing hypothesis is that “unopposed

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estrogen”— estrogen not counterbalanced by progesterone, drives EC development [2,3]. However, accumulating evidence suggests that insulin resistance is a risk factor of EC. Diseases associated with insulin resistance, such as obesity, type II diabetes mellitus [4] and polycystic ovary syndrome (PCOS) [5], have been named risk factors for EC. Insulin resistance, a condition in which target tissues have decreased sensitivity to insulin, leads to elevated blood insulin and glucose levels. This prediabetic state plays an important role in the development and progression of some types of cancers [6], including breast cancer, colorectal cancer, prostate cancer, pancreatic cancer and EC. In this review, we summarize the epidemiological and molecular evidence linking insulin resistance and EC. Further, we discuss useful biomarkers for studying the relationship between these conditions and review therapies for insulin resistance and their potential applications in EC. Epidemiological evidence of insulin resistance as a risk factor of EC The insulin-resistant state is defined by reduced sensitivity of insulin-responsive tissues to insulin, which results in increased levels of glucose in the blood. To overcome this, β cells produce more insulin, resulting in compensatory hyperinsulinemia. Because insulin has many physiological functions, increased concentrations of this protein can induce adverse effects, including cancer formation. In a prospective study, researchers found that fasting insulin levels of women not using hormone therapy were positively associated with EC risk, and hyperinsulinemia was reported as a risk factor of EC independent of estradiol [7]. Another prospective study demonstrated that insulin resistance was highly prevalent in endometrial cancer patients, including non-obese women [8]. Furthermore, insulin resistance has been suggested to positively correlate with the stage of disease and local and regional tumor dissemination in EC patients [9]. There is also accumulating evidence that diseases associated with insulin resistance are risk factors for EC. Several large scale prospective studies have indicated that high body mass index (BMI), which could indicate obesity, is correlated to increased risk of EC [10,11]. In addition, upper body fat distribution, which was evaluated by waist circumference and waist:hip ratio was also strongly associated with EC, and this association still remained after adjustment for BMI [12]. Weight gain during adulthood, especially the peri-menopausal period, was also found to increase EC risk in women, regardless of whether they were obese or not [13]. In addition, obesity has been associated with poor prognosis in EC patients [14]. Type II diabetes mellitus is also purportedly strongly associated with EC [4], and this observation was confirmed by a meta-analysis showing that diabetes increased EC risk [15]. Similarly, a 31 year follow-up study suggested that PCOS patients are at increased risk for EC [5]. Feamley et al. found that women with PCOS were four times more likely to develop EC than women without PCOS [16]. Furthermore, a prospective cohort study [17] and a retrospective case–control study [18] indicated that metabolic syndrome is a very important risk factor of EC. EC patients are primarily peri- and post-menopausal women, but some patients are 40 years of age or younger. Compared with controls of the same age group, Haidopoulos et al. found that young EC patients had significantly higher BMIs (≥30 kg/m 2) [19]. In a retrospective cohort study, Soliman et al. found that 58% of young EC patients had BMIs indicating obesity (≥30 kg/m 2) [20]. Furthermore, Schmeler et al. suggested that PCOS is more prevalent in young, normal-weight (BMI b 25 kg/m 2) EC patients [21]. Thus, as both obesity and PCOS are associated with insulin resistance, insulin resistance seems to play an important role in the development of EC in young women. Lynch syndrome, an autosomal and dominantly inherited disease attributed to a defect in mismatch repair, also places young women at increased risk for EC. In their study

population, Schmeler et al. found that 12% of overweight EC patients had Lynch syndrome, whereas only 4% of the normal-weight EC patients suffered from this disease [21]. Similarly, our group found that obesity was more prevalent in Lynch syndromeassociated EC cases than in non-Lynch syndrome-associated cases [22]. Accordingly, obesity is likely involved in the development of Lynch syndrome-related EC. Taken together, these findings suggest that insulin resistance at least partially contributes to the development of EC. Molecular correlates of insulin resistance and EC Insulin resistance and EC development are regulated by common molecular factors, including mediators of inflammation, adipokines and excessive androgen. Inflammation has been reported to induce insulin resistance by inhibiting insulin signaling and promoting free fatty acid release from adipose tissue. In this process, macrophages recruited to adipose tissue by monocyte chemoattractant protein-1 (MCP-1) [23] or hypoxia [23,24] and secrete tumor necrosis factorα (TNF-α), which induces lipolysis and inhibits the insulin signaling pathway via activation of the extracellular signal-related kinase (ERK) and c-Jun-N-terminal-kinase (JNK) pathways [25,26]. This blockage of insulin signaling results in the release of free fatty acids from adipose tissue, leading to decreased glucose uptake and increased serine phosphorylation of insulin receptor substrate-1 (IRS1) [27] consistent with insulin resistance. Furthermore, the presence of excessive adipose tissue results in high levels of non-esterified fatty acid levels, which promote fatty acid oxidation and increase the production of reactive oxygen species resulting in the inhibition of the insulin signaling pathways through the activation of JNK [28]. These events work together to promote the development of insulin resistance, which, in turn, encourages further free fatty acid release [29], thereby establishing a self-promoting cycle (Fig. 1). In addition to secreting TNF-α, macrophages recruited to adipose tissue also secrete interleukin-6 (IL-6), which contributes to the development of an insulin-resistant state through a mechanism that is not yet clear [30]. Notably, TNF-α and IL-6 were also found to increase the production of estrogen in both normal and malignant breast tissues [31]. A prospective study including post-menopausal women not using hormones showed that C-reactive protein (CRP), an inflammatory biomarker induced by IL-6, was a risk factor of EC. This risk may partially be explained by hyperinsulinemia and elevated estradiol levels since adjustment for estradiol and insulin attenuated the association between inflammation and EC. Furthermore, inflammation characterized by high levels of CRP, excessive estradiol and hyperinsulinemia may be involved in the association between obesity and EC. However, no association between EC and TNF-α or IL-6 was found, suggesting that these proinflammatory cytokines may work locally [32]. Adipose tissue, the site of inflammation-induced insulin resistance, is also the predominant source of aromatase, which has been reported to convert androgens to estrogens [33]. In this conversion process, androgens undergo hydroxylation at the 19-methyl group, cleavage of the C10\C19 bond and aromatization of the A ring to form estrogens [34]. The result is increased estrogen release into the circulation which drives EC pathogenesis as explained by the “unopposed estrogen” hypothesis. The adipokines adiponectin, leptin and plasminogen activator inhibitor-1 (PAI-1), cytokines secreted by adipose tissue, also play important roles in the development of both insulin resistance and EC. Adiponectin was reported to reduce serum glucose concentration in vivo by promoting activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) [35]. Activated PPAR-α also increases the expression of both adiponectin and adiponectin receptors resulting in amelioration of obesity-related insulin resistance [36]. Several studies show that

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Fig. 1. Development of insulin resistance in the form of a self-promoting cycle.

adiponectin is strongly correlated with EC [37,38]. Both isoforms of adiponectin receptor, adipo-R1 and adipo-R2, are expressed in epithelial and stromal cells of normal endometrial tissue and HEC-1-A and RL95-2 EC cells [39,40]. Furthermore, adiponectin treatment induced apoptosis in HEC-1-A and RL95-2 cells suggesting that adiponectin has a protective effect against EC [40]. Leyva et al. reported that there is a strong association between blood levels of the adipokine leptin and insulin resistance [41]. Leptin has been shown to decrease the response to insulin by inhibiting signaling through insulin receptor (IR) [42] and increasing the activity of Na +/H + exchanger-1 [43], which has been found to increase insulin sensitivity in vivo when inhibited [44]. Furthermore, Gao et al. found that both isoforms of the leptin receptor, Ob-R1 and Ob-R2, are expressed in the Ishikawa, ECC-1, HEC-1-A, HEC-1-B, RL95-2 and AN3CA EC cell lines [45]. Functionally, leptin has been reported to stimulate proliferation and promote invasiveness of EC cells [45–47]. The multifunctional adipokine PAI-1 is considered a risk factor of insulin resistance [48], and was reportedly independently associated with increased risk of metabolic syndrome [49]. Notably, PAI-1 levels were found to be significantly higher in cancerous tissue than in normal tissue, and these increased levels were strongly related to shorter disease-free and overall survival in clinical studies [50]. In early stage EC patients (phases I–II), high PAI-1 level was associated with short progression-free survival [51]. Interestingly, there have been many controversial experimental and clinical findings concerning EC development that cannot be explained by the “unopposed estrogen” hypothesis. First, EC occurs primarily in peri- and post-menopausal women with estrogen disorders or deficiency. Second, late menopause and long duration of fertile life in women was inversely associated with the risk for cancers of the upper gastrointestinal tract, breast and endometrium [52–54]. Similarly, a daily dose of conjugated equine estrogen was

associated with decreased breast cancer risk [55]. Finally, estrogen deficiency was first reported as a cancer risk factor for females who are non-smokers, non-drinkers, elderly and post-menopausal among oral cancer patients [56]. These collective results may be partially explained by the observation that insulin resistance and compensatory hyperinsulinemia provoke androgen synthesis at the expense of estrogen production [52]. An in vivo study using aromatase knockout mice showed that these animals were insulin resistant with decreased glucose oxidation, increased adiposity and high insulin levels. When estrogen treatment was applied, the glucose intolerance of the mice was ameliorated [57]. Solomon et al. found that long or highly irregular menstrual cycles, which suggest functional deficiencies of the ovaries, placed women at increased risk for type II diabetes, and obesity could not completely explain this increased risk [58]. Among post-menopausal women whose ovaries ceased working, the loss of ovarian function was suggested to be associated with hyperisulinemia [59]. Thus, the interplay between insulin resistance and estrogen deficiency may illuminate a distinctive mechanism of cancer development [52]. However, little information about the association between insulin resistance, estrogen deficiency and EC is available. Interactions between insulin resistance and estrogen deficiency and their role in the initiation, progression, and prevention of EC warrant further investigation. These studies collectively show that the molecular risk factors of insulin resistance are also risk factors of EC. This suggests that the development of insulin resistance and EC may be promoted simultaneously in the body. Effects of insulin on EC development The increase in insulin levels induced as a result of insulin resistance can trigger many physiological effects that may drive EC development. Insulin is a well defined growth factor that exerts its effects

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in many cell types through interaction with both cognate and noncognate receptors. Our group found that Ishikawa 3-H-12 EC cells express IR, and treating these cells with insulin induced proliferation and inhibited apoptosis in a dose- and time-dependent manner. These mitogenic and anti-apoptotic effects were likely due to insulin signaling via IR, its cognate receptor [60]. Upon insulin binding, IR, is activated, triggering activation of IRS-1, which then activates the PI3K and mitogen-activated protein kinase (MAPK) pathways. The PI3K/ Akt pathway targets several key proteins that regulate lipid and carbohydrate metabolism as well as cell proliferation and apoptosis [61], and activated MAPKs regulate cell proliferation and survival [62]. These two insulin signaling pathways are known to play an important role in carcinogenesis [63]. An investigation involving six EC cell lines revealed that up-regulation of either the PI3K/Akt or Ras/MAPK signaling pathways was significant for the development of the majority of EC [64]. In addition, an analysis of signaling systems in the cancer genome revealed that there is a strong correlation between the PI3K signaling pathway and EC [65]. Phosphatase and tensin homolog detected on chromosome 10 (PTEN) inactivation, which results in PI3K/Akt pathway activation [66], and p27 (KIP1) expression are specific features of EC progression in obese EC patients [67]. Furthermore, Akt was suggested to inhibit the activation of AMPK [68], which inhibits the mammalian target of rapamycin (mTOR) pathway through phosphorylation of tuberous sclerosis complex-2 (TSC-2) [69], and co-signaling molecules that bind mTOR [70]. Overactivation of mTOR is common in EC tissues and some EC cell lines (AN3CA, HEC-1-A, HEC-1-B, Ishikawa and RL95-2) [71]. In vivo, the MAPK signaling pathway has been found to mediate estradiol induced proliferation of Ishikawa EC cells [72]. Furthermore, activation of the MAPK signaling pathway induced up-regulation of survivin, which regulates the proliferation of Ishikawa EC cells [73]. IR and insulin like growth factor-1 (IGF-1) receptor are partly homologous. Therefore, insulin can bind to IGF-1 receptor to activate signaling pathways such as PI3K/Akt and Ras/MAPK [74,75]. Once activated, the PI3K and MAPK pathways can activate transcriptional activation function-1 (TAF-1) of estrogen receptor, which regulates cell growth and division [76]. An in vitro study showed that insulin can inhibit insulin like growth factor binding protein-1 (IGFBP-1) mRNA and protein expression in a dosedependent manner in endometrial stromal cells [77]. Decreased IGFBP-1 results in elevated levels of free IGF-1, a potent mitogen and survival factor, which can thus promote the development of EC. Kashima et al. showed that estrogen induced autocrine effects of IGF-1 in Ishikawa cells [72]. Moreover, cross-talk between IGF-1 receptor and estrogen receptor signaling plays an important role in the development of breast cancer, which shares similar risk factors with EC [78]. These in vitro studies suggest that the insulin, IGF-1 and estrogen signaling network may promote the development of EC. However, there is limited clinical information on these relationships. Although estrogen and insulin have been suggested as important risk factors of EC, the role of IGF-1 in EC development is still uncertain. An analysis including 17 prospective studies revealed that circulating IGF-1 levels are positively correlated with risk of breast cancer [79]. However, the relationship between circulating IGF-1 levels and EC remains controversial, with some studies showing an inverse association [80,81], no association [10,82], or even a positive association [83]. Thus, further investigation is needed to clarify this relationship. Insulin also promotes the development of EC in less direct ways. Insulin has been reported to inhibit the synthesis of sex hormone binding globulin (SHBG), which tightly binds and regulates the activity of sex hormones [84]. Thus, when insulin levels increase due to insulin resistance, this inhibition results in an increase in free sex hormone levels. Notably, insulin also promotes the synthesis of androgens in the ovaries. Epidemiological studies showed that

obese women had high blood estradiol and testosterone levels and low blood SHBG levels [85]. Increased free androgens supply more substrate for peripheral estrogen conversion, which is especially dangerous for postmenopausal women. After menopause, the ovaries cease to produce estrogen and progesterone, making peripheral estrogen conversion the main source of estrogen in the circulation [86]. Without the protection of progesterone, excessive estrogens promote the development of EC as described by the “unopposed estrogen” hypothesis. For premenopausal women, increased levels of androgen induce anovulation [87], resulting in insufficient progesterone to counterbalance the proliferation promoting and antiapoptotic effects of estrogen. In accordance with this, clinical investigations show that women with PCOS, which is characterized by obesity, anovulation, hyperinsulinemia and high serum androgen level, face increased EC risk [88]. Li et al. found that progesterone receptor expression in the hyperplastic endometrial stroma of women with PCOS was significantly lower than in women without PCOS, which indicates decreased protection of progesterone [89]. Alterations in circulating SHBG, IGF-1 and estrogen levels induced by hyperinsulinemia and hyperandrogenism are purported to underlie neoplastic changes in the endometrium of PCOS patients [90,91]. Thus, insulin resistance, which induces changes in blood estrogen and androgen levels, plays important indirect roles in the development of EC. Promising biomarkers to evaluate the relationship of insulin resistance and EC Despite our growing understanding of insulin resistance, EC and the association between these conditions, the existing methods used to study this complex relationship are not well defined. For example, insulin resistance is often assessed by different approaches in epidemiological studies including the homeostasis model assessmentinsulin resistance (HOMA-IR) index [fasting insulin (μIU/mL) × fasting glucose (mmol/L) / 22.5] [7], quantitative insulin sensitivity check index (QUICKI) [1 / (log fasting insulin + log fasting glucose), with a value of 0.357 indicating insulin resistance] [8], and insulin resistance index [fasting plasma glucose (mmol/L) × fasting insulin (μIU/mL)/25, with a value of 4.8 or more indicating insulin resistance] [9]. Furthermore, some epidemiological studies also do not supply a threshold to identify the association between insulin resistance and EC. Thus, we failed to find a widely accepted method to evaluate the association between insulin resistance and EC. To further improve our understanding of these conditions and their underlying link, a standardized approach is needed for future studies. Therefore, based on reports in recent years, we suggest that adiponectin and C-peptide may be promising biomarkers to evaluate the relationship between these conditions. Adiponectin, which is exclusively produced by adipocytes, was inversely correlated with hyperinsulinemia and the degree of insulin resistance independent of adiposity [92]. Furthermore, a decrease in adiponectin levels was considered a marker of developing insulin resistance [93]. Using blood samples collected from 105 obese women, Rzwpka-Gorska I et al. found that the serum adiponectin concentration of subjects with EC was significantly lower than those with atypical endometrial hyperplasia or normal endometrium. Furthermore, an inverse correlation was observed between circulating levels of adiponectin and cancer grade [37]. Evidence from another study suggested that the concentration of adiponectin in the circulation of EC patients was lower than in controls and that insulin resistance was independently correlated with EC [94]. Consistent with this, high adiponectin levels were reported to be correlated with decreased EC risk [38], and this effect of adiponectin on EC was independent of other known EC risk factors [94–96]. Thus, adiponectin may be a favorable index with which to evaluate the effects of insulin resistance on EC.

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Fig. 2. Central role of insulin resistance plays in the development of endometrial cancer.

C-peptide is released simultaneously and in equal concentration with insulin. Thus, in response to insulin resistance, increased levels of both insulin and C-peptide are released to overcome this state. However, compared with insulin, C-peptide is not often susceptible to individual variation in hepatic clearance and has a longer half-life in plasma. Several studies investigated the relationship between C-peptide and EC. Some indicate that there is a positive association between circulating C-peptide concentrations and EC [10,97] but a negative association [98] has also been reported. The studies in which a positive correlation was found were designed prospectively and suggested that insulin resistance contributes to EC pathogenesis. However, those studies only compared the serum C-peptide or insulin concentrations between cases and controls, and there was no standardized threshold of C-peptide level with which to evaluate the relationship between insulin resistance and EC risk. Nevertheless, the results suggested that serum C-peptide level changes before EC pathogenesis occurs and that high blood C-peptide level is associated with EC pathogenesis. Therefore, C-peptide may be a promising index for evaluating the effects of insulin resistance on EC.

estriol, progesterone and ergocryptine to treat five young women who were diagnosed with EC (stage IA, type I) pathologically. After six months of therapy and in two years of follow-up, histopathology results showed normal endometrium [104]. Although not the only agent used in this study, metformin probably had at least a partial effect in this therapeutic strategy. Thus, metformin may have potential as a novel EC therapy [105]. Large-scale clinical studies in the future will help further evaluate this drug in treating EC. Insulin administration is also a long-standing therapy for type II diabetes. However, several studies showed that insulin injection increased the risk of colorectal cancer, a disease also related to insulin resistance [106,107]. Accordingly, we must consider whether the carcinogenesis of this disease is at least partly related to excessive insulin stimulation. Considering insulin resistance can also cause excessive insulin stimulation, insulin may also promote the pathogenesis of EC. Nevertheless, the relationship between insulin administration and EC risk is unknown.

Conclusion Therapies for insulin resistance and their potential applications in EC Insulin-sensitizing agents have been used to treat type II diabetes mellitus for decades. Metformin, a common insulin-sensitizing drug, inhibits glucose and lipid synthesis in the liver and increases glucose uptake in the muscles. As a result, less insulin is needed to regulate serum glucose level, thereby ameliorating insulin resistance through a mechanism involving AMPK [99]. In addition to its effects on type II diabetes, metformin has increasingly been shown to have anti-cancer effects [100]. A review previously summarized that metformin is a promising option for breast cancer treatment [101], but there are limited reports about the application of metformin for EC treatment. In an in vitro study, metformin was reported to inhibit the growth of ECC-1 and Ishikawa EC cells in a dose-dependent manner via activation of AMPK and inhibition of mTOR [102]. Additionally, in a case report published in 2003, metformin was applied in the treatment of a 37-year-old patient who was diagnosed with endometrial hyperplasia, a precancerous lesion of EC. After one month of metformin therapy, the lesion regressed [103]. In another small scale study, metformin was used with

In summary, there is accumulating epidemiological and molecular evidence that insulin resistance is a significant risk factor of EC. Risk factors of insulin resistance, such as inflammatory mediators, adipokines, and excessive androgens are also risk factors of EC. Activation of their signaling pathways is responsible for the development of insulin resistance as well as EC. In the state of insulin resistance, insulin, which is present at elevated levels, directly and indirectly impacts the development of EC. The direct mechanism involves activation of key signaling pathways including PI3K/Akt and Ras/MAPK and signaling pathway crosstalk among insulin, IGF-1 and estrogen. In the indirect mechanism, excess insulin results in low blood SHBG levels and high blood estrogen and androgen levels, which in turn promote the development of EC. Taken together, these studies suggest that insulin resistance plays a central role in EC carcinogenesis (Fig. 2) and may be a novel preventive and therapeutic target for EC. Indeed, body weight control and treatment with insulin-sensitizing agents seem to be effective preventive strategies. However, information about the application of insulinsensitizing agents for EC is very limited at present. The topic of

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insulin resistance and its role in EC warrants further attention in the future. Conflict of interest statement None declared.

Acknowledgment We would like to thank Jheri Dupart for her editorial assistance. The authors' work is funded by Natural Science Fund of China (30772316) and Specialized Research Fund for the Doctoral Program of Higher Education of China (20070062006). References [1] Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–36. [2] Henderson BE, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer. Cancer Res 1982;42:3232–9. [3] Key TJ, Pike MC. The dose–effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 1988;57:205–12. [4] Saltzman BS, Doherty JA, Hill DA, et al. Diabetes and endometrial cancer: an evaluation of the modifying effects of other known risk factors. Am J Epidemiol 2008;167:607–14. [5] Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil (Camb) 2000;3:101–5. [6] Godsland IF. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin Sci (Lond) 2010;118:315–32. [7] Gunter MJ, Hoover DR, Yu H, et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17:921–9. [8] Burzawa JK, Schmeler KM, Soliman PT, et al. Prospective evaluation of insulin resistance among endometrial cancer patients. Am J Obstet Gynecol 2011; 204(355):e1–7. [9] Berstein LM, Kvatchevskaya JO, Poroshina TE, et al. Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol 2004;130:687–93. [10] Lukanova A, Zeleniuch-Jacquotte A, Lundin E, et al. Prediagnostic levels of Cpeptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. Int J Cancer 2004;108:262–8. [11] Allen NE, Key TJ, Dossus L, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 2008;15:485–97. [12] Xu WH, Matthews CE, Xiang YB, et al. Effect of adiposity and fat distribution on endometrial cancer risk in Shanghai women. Am J Epidemiol 2005;161:939–47. [13] Xu WH, Xiang YB, Zheng W, et al. Weight history and risk of endometrial cancer among Chinese women. Int J Epidemiol 2006;35:159–66. [14] Chia VM, Newcomb PA, Trentham-Dietz A, Hampton JM. Obesity, diabetes, and other factors in relation to survival after endometrial cancer diagnosis. Int J Gynecol Cancer 2007;17:441–6. [15] Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007;50:1365–74. [16] Fearnley EJ, Marquart L, Spurdle AB, Weinstein P, Webb PM. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case–control study. Cancer Causes Control 2010;21:2303–8. [17] Bjorge T, Stocks T, Lukanova A, et al. Metabolic syndrome and endometrial carcinoma. Am J Epidemiol 2010;171:892–902. [18] Zhang Y, Liu Z, Yu X, et al. The association between metabolic abnormality and endometrial cancer: a large case–control study in China. Gynecol Oncol 2010;117:41–6. [19] Haidopoulos D, Simou M, Akrivos N, et al. Risk factors in women 40 years of age and younger with endometrial carcinoma. Acta Obstet Gynecol Scand 2010;89: 1326–30. [20] Soliman PT, Oh JC, Schmeler KM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105:575–80. [21] Schmeler KM, Soliman PT, Sun CC, Slomovitz BM, Gershenson DM, Lu KH. Endometrial cancer in young, normal-weight women. Gynecol Oncol 2005;99:388–92. [22] Wang Y, Xue F, Broaddus RR, Tao X, Xie SS, Zhu Y. Clinicopathological features in endometrial carcinoma associated with Lynch syndrome in China. Int J Gynecol Cancer 2009;19:651–6. [23] Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821–30. [24] Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007;56:901–11. [25] Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 2003;27(Suppl. 3):S53–5. [26] Souza SC, Palmer HJ, Kang YH, et al. TNF-alpha induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocytes. J Cell Biochem 2003;89:1077–86.

[27] Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000;106: 171–6. [28] Nishikawa T, Araki E. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 2007; 9:343–53. [29] Wassink AM, Olijhoek JK, Visseren FL. The metabolic syndrome: metabolic changes with vascular consequences. Eur J Clin Invest 2007;37:8–17. [30] Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010;72:219–46. [31] Purohit A, Newman SP, Reed MJ. The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 2002;4: 65–9. [32] Wang T, Rohan TE, Gunter MJ, et al. A prospective study of inflammation markers and endometrial cancer risk in postmenopausal hormone nonusers. Cancer Epidemiol Biomarkers Prev 2011;20:971–7. [33] Longcope C, Baker Jr R, Johnston CC. Androgen and estrogen metabolism: relationship to obesity. Metabolism 1986;35:235–7. [34] Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S. Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Mol Endocrinol 2007;21:401–14. [35] Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13:332–9. [36] Tsuchida A, Yamauchi T, Takekawa S, et al. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 2005;54:3358–70. [37] Rzepka-Gorska I, Bedner R, Cymbaluk-Ploska A, Chudecka-Glaz A. Serum adiponectin in relation to endometrial cancer and endometrial hyperplasia with atypia in obese women. Eur J Gynaecol Oncol 2008;29:594–7. [38] Cust AE, Kaaks R, Friedenreich C, et al. Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J Clin Endocrinol Metab 2007;92:255–63. [39] Takemura Y, Osuga Y, Yamauchi T, et al. Expression of adiponectin receptors and its possible implication in the human endometrium. Endocrinology 2006;147: 3203–10. [40] Cong L, Gasser J, Zhao J, Yang B, Li F, Zhao AZ. Human adiponectin inhibits cell growth and induces apoptosis in human endometrial carcinoma cells, HEC-1-A and RL95 2. Endocr Relat Cancer 2007;14:713–20. [41] Leyva F, Godsland IF, Ghatei M, et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol 1998;18: 928–33. [42] Burgos-Ramos E, Chowen JA, Arilla-Ferreiro E, Canelles S, Argente J, Barrios V. Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3. J Neurochem 2011;117:175–85. [43] Sarigianni M, Bekiari E, Tsapas A, Kaloyianni M, Koliakos G, Paletas K. Effect of leptin and insulin resistance on properties of human monocytes in lean and obese healthy participants. Angiology 2010;61:768–74. [44] Sarigianni M, Tsapas A, Mikhailidis DP, Kaloyianni M, Koliakos G, Paletas K. Involvement of signaling molecules on na/h exchanger-1 activity in human monocytes. Open Cardiovasc Med J 2010;4:181–8. [45] Gao J, Tian J, Lv Y, et al. Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci 2009;100:389–95. [46] Sharma D, Saxena NK, Vertino PM, Anania FA. Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer 2006;13:629–40. [47] Catalano S, Giordano C, Rizza P, et al. Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol 2009;218:490–500. [48] Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Draz HM. Relationship between resistin and aPAI-1 levels with insulin resistance in Saudi children. Pediatr Int 2010;52:551–6. [49] Chou YY, Sheu WH, Tang YJ, et al. Plasminogen activator inhibitor type 1 (PAI-1) is a valuable biomarker for predicting the metabolic syndrome (MS) in institutionalized elderly residents in Taiwan. Arch Gerontol Geriatr 2009;49(Suppl. 2): S41–5. [50] Tecimer C, Doering DL, Goldsmith LJ, Meyer JS, Abdulhay G, Wittliff JL. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer. Gynecol Oncol 2001;80:48–55. [51] Fredstorp-Lidebring M, Bendahl PO, Brunner N, et al. Urokinase plasminogen activator and its inhibitor, PAI-1, in association with progression-free survival in early stage endometrial cancer. Eur J Cancer 2001;37:2339–48. [52] Suba Z. Interplay between insulin resistance and estrogen deficiency as coactivators in carcinogenesis. Pathol Oncol Res 2011;18:123–33. [53] Freedman ND, Lacey JJ, Hollenbeck AR, Leitzmann MF, Schatzkin A, Abnet CC. The association of menstrual and reproductive factors with upper gastrointestinal tract cancers in the NIH–AARP cohort. Cancer 2010;116:1572–81. [54] Britt K, Ashworth A, Smalley M. Pregnancy and the risk of breast cancer. Endocr Relat Cancer 2007;14:907–33. [55] Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701–12. [56] Suba Z. Gender-related hormonal risk factors for oral cancer. Pathol Oncol Res 2007;13:195–202.

N. Mu et al. / Gynecologic Oncology 125 (2012) 751–757 [57] Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 2000;97:12735–40. [58] Solomon CG, Hu FB, Dunaif A, et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 2001;286:2421–6. [59] Proudler AJ, Felton CV, Stevenson JC. Ageing and the response of plasma insulin, glucose and C-peptide concentrations to intravenous glucose in postmenopausal women. Clin Sci (Lond) 1992;83:489–94. [60] Zhao J, Xue FX, Hua SF, Zhang LZ. Effects of insulin on proliferation and apoptosis of endometrial carcinoma cell. Zhonghua Fu Chan Ke Za Zhi 2007;42:696–700. [61] Funaki M, Katagiri H, Inukai K, Kikuchi M, Asano T. Structure and function of phosphatidylinositol-3,4 kinase. Cell Signal 2000;12:135–42. [62] Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 1993;268:14553–6. [63] Mussig K, Haring HU. Insulin signal transduction in normal cells and its role in carcinogenesis. Exp Clin Endocrinol Diabetes 2010;118:356–9. [64] Ogawa K, Sun C, Horii A. Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. Oncol Rep 2005;14:1481–5. [65] Salvesen HB, Carter SL, Mannelqvist M, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci USA 2009;106:4834–9. [66] Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 2001;114:2903–10. [67] Dellas A, Jundt G, Sartorius G, Schneider M, Moch H. Combined PTEN and p27kip1 protein expression patterns are associated with obesity and prognosis in endometrial carcinomas. Clin Cancer Res 2009;15:2456–62. [68] Horman S, Vertommen D, Heath R, et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 2006;281: 5335–40. [69] Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577–90. [70] Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214–26. [71] Lu KH, Wu W, Dave B, et al. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 2008;14:2543–50. [72] Kashima H, Shiozawa T, Miyamoto T, et al. Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E. Endocr Relat Cancer 2009;16:113–22. [73] Ai Z, Yin L, Zhou X, et al. Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer 2006;107:746–56. [74] Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K. Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J 1997;327(Pt 1):209–15. [75] Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004;4:505–18. [76] Kato S, Masuhiro Y, Watanabe M, et al. Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways. Genes Cells 2000;5:593–601. [77] Lathi RB, Hess AP, Tulac S, Nayak NR, Conti M, Giudice LC. Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 2005;90:1599–606. [78] Fagan DH, Yee D. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008;13:423–9. [79] Key TJ, Appleby PN, Reeves GK, Roddam AW. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 2010;11:530–42. [80] Lacey Jr JV, Potischman N, Madigan MP, et al. Insulin-like growth factors, insulinlike growth factor-binding proteins, and endometrial cancer in postmenopausal women: results from a U.S. case–control study. Cancer Epidemiol Biomarkers Prev 2004(13):607–12. [81] Petridou E, Koukoulomatis P, Alexe DM, Voulgaris Z, Spanos E, Trichopoulos D. Endometrial cancer and the IGF system: a case–control study in Greece. Oncology 2003;64:341–5.

757

[82] Augustin LS, Dal Maso L, Franceschi S, et al. Association between components of the insulin-like growth factor system and endometrial cancer risk. Oncology 2004;67:54–9. [83] Waksmanski B, Dudkiewicz J, Dabrowski S. Function of insulin-like growth factor (IGF-I) and its binding protein (IGFBP-1) in pathological proliferation of endometrium. Wiad Lek 2001;54:656–61. [84] Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 1988;67:460–4. [85] Baglietto L, English DR, Hopper JL, et al. Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res Treat 2009;115:171–9. [86] Vermeulen A, Verdonck L. Sex hormone concentrations in post-menopausal women. Clin Endocrinol (Oxf) 1978;9:59–66. [87] Diamanti-Kandarakis E, Papailiou J, Palimeri S. Hyperandrogenemia: pathophysiology and its role in ovulatory dysfunction in PCOS. Pediatr Endocrinol Rev 2006;3(Suppl. 1):198–204. [88] Navaratnarajah R, Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer. Semin Reprod Med 2008;26:62–71. [89] Li L, Yang C, Qiaojie. Pathological and immunohistochemical study on estrogen and progesterone receptors in endometrium of polycystic ovarian syndrome. Zhonghua Fu Chan Ke Za Zhi 1998;33:89–91. [90] Gibson M. Reproductive health and polycystic ovary syndrome. Am J Med 1995;98:67S–75S. [91] Meirow D, Schenker JG. The link between female infertility and cancer: epidemiology and possible aetiologies. Hum Reprod Update 1996;2:63–75. [92] Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930–5. [93] Tajtakova M, Petrasova D, Pidanicova A, Gallovicova A, Blanarova C, Petrovicova J. Serum levels of leptin, adiponectin, retinol binding protein 4 and leptin/adiponectin molar ratio as another possible marker of insulin resistance in obese. Bratisl Lek Listy 2010;111:212–5. [94] Soliman PT, Wu D, Tortolero-Luna G, et al. Association between adiponectin, insulin resistance, and endometrial cancer. Cancer 2006;106:2376–81. [95] Petridou E, Mantzoros C, Dessypris N, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case–control study in Greece. J Clin Endocrinol Metab 2003;88:993–7. [96] Dal Maso L, Augustin LS, Karalis A, et al. Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab 2004;89:1160–3. [97] Cust AE, Allen NE, Rinaldi S, et al. Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition. Int J Cancer 2007;120:2656–64. [98] Troisi R, Potischman N, Hoover RN, Siiteri P, Brinton LA. Insulin and endometrial cancer. Am J Epidemiol 1997;146:476–82. [99] Schimmack G, Defronzo RA, Musi N. AMP-activated protein kinase: role in metabolism and therapeutic implications. Diabetes Obes Metab 2006;8:591–602. [100] Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol 2011; [Epub ahead of print, PMID:21301998]. [101] Gonzalez-Angulo AM, Meric-Bernstam F. Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 2010;16:1695–700. [102] Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy. Gynecol Oncol 2010;116:92–8. [103] Session DR, Kalli KR, Tummon IS, Damario MA, Dumesic DA. Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent. Gynecol Endocrinol 2003;17:405–7. [104] Stanosz S. An attempt at conservative treatment in selected cases of type I endometrial carcinoma (stage I a/G1) in young women. Eur J Gynaecol Oncol 2009; 30:365–9. [105] Mu N, Wang Y, Xue F. Metformin: a potential novel endometrial cancer therapy. Int J Gynecol Cancer 2012;22:181. [106] Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044–50. [107] Chung YW, Han DS, Park KH, Eun CS, Yoo KS, Park CK. Insulin therapy and colorectal adenoma risk among patients with type 2 diabetes mellitus: a case– control study in Korea. Dis Colon Rectum 2008;51:593–7.