Cytokine & Growth Factor Reviews 24 (2013) 503–513

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Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr

Mini review

Role of adipokines and cytokines in obesity-associated breast cancer: Therapeutic targets Sajid Khan, Samriddhi Shukla, Sonam Sinha, Syed Musthapa Meeran * Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India

A R T I C L E I N F O

A B S T R A C T

Article history: Available online 21 October 2013

Obesity is the cause of a large proportion of breast cancer incidences and mortality in post-menopausal women. In obese people, elevated levels of various growth factors such as insulin and insulin-like growth factors (IGFs) are found. Elevated insulin level leads to increased secretion of estrogen by binding to the circulating sex hormone binding globulin (SHBG). The increased estrogen-mediated downstream signaling favors breast carcinogenesis. Obesity leads to altered expression profiles of various adipokines and cytokines including leptin, adiponectin, IL-6, TNF-a and IL-1b. The increased levels of leptin and decreased adiponectin secretion are directly associated with breast cancer development. Increased levels of pro-inflammatory cytokines within the tumor microenvironment promote tumor development. Efficacy of available breast cancer drugs against obesity-associated breast cancer is yet to be confirmed. In this review, we will discuss different adipokine- and cytokine-mediated molecular signaling pathways involved in obesity-associated breast cancer, available therapeutic strategies and potential therapeutic targets for obesity-associated breast cancer. ß 2013 Elsevier Ltd. All rights reserved.

Keywords: Obesity Breast cancer Leptin Adiponectin Cytokines

1. Introduction Breast cancer is the most common type of cancer and also the leading cause of cancer-related deaths in women, worldwide.

Abbreviations: IGFs, insulin-like growth factors; SHBG, sex hormone binding globulin; BMI, body mass index; IGFBPs, IGF binding proteins; IGF-1R, insulinlike growth factor-1 receptor; CLS, crown-like structure; NFkB, nuclear factor kappa-B; STAT3, signal transducer and activator of transcription-3; COX-2, cyclooxygenase-2; TNF-a, tumor necrosis factor-a; ILs, interleukins; IFNs, interferons; JNK, c-Jun N-terminal kinase; SOCS3, suppressor of cytokine signaling-3; JAK2, Janus kinase-2; MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor-2; ERa, estrogen receptor-a; ERK, extracellular signal-regulated kinase; HER-2, human epidermal growth factor receptor-2; hTERT, human telomerase reverse transcriptase; PARP, poly (ADP-ribose) polymerase; AMPK, AMP-activated protein kinase; LDL, low-density lipoprotein; PDGF-BB, platelet-derived growth factor subunit B homodimer; bFGF, basic fibroblast growth factor; HB-EGF, heparinbinding epidermal growth factor-like growth factor; GSK-3b, glycogen synthase kinase-3b; HIF-1a, hypoxia-inducible factor-1a; C/EBPa, CCAAT/enhancer binding protein-a; PFS, progression-free survival; CDK, cyclin-dependent kinase; PEGLPrA2, pegylated leptin peptide receptor antagonist 2; mTOR, mammalian target of rapamycin; EGCG, epigallocatechin-3-gallate; NSAIDs, non-steroidal anti-inflammatory drugs; PPARa, peroxisome proliferator-activated receptor-a. * Corresponding author at: Division of Endocrinology, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extn., Sector-10, Sitapur Road, Lucknow 226 031, India. Tel.: +91 522 2612411x4491; fax: +91 522 2623938. E-mail addresses: [email protected], [email protected] (S.M. Meeran). 1359-6101/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2013.10.001

According to GLOBOCAN 2008, breast cancer accounted for 23% (1.38 million) of the total new cancer cases and 14% (458,000) of total cancer-related deaths in the year 2008 [1]. Several reproductive and lifestyle factors are associated with the development of breast cancer. Among the reproductive factors are long menstrual history, nulliparity, increased use of oral contraceptives, and giving birth to a child at later age [2]. Lifestyle factors including less physical activity, consumption of high calorie diets, cigarette smoking and alcohol consumption are strongly associated with increased risk of breast cancer development [3,4]. Obesity is an abnormal or excessive fat accumulation in adipose tissue which leads to impaired health [5]. According to World Health Organization (WHO), obesity is defined as having a body mass index (BMI) of equal to or higher than 30 kg/m2. It is the major cause of onset of a number of diseases such as type-2 diabetes, cardiovascular diseases (CVDs), infertility, and several types of cancers [6]. It is estimated that 25–30% of cancers at numerous sites such as esophagus, pancreas, colorectum, endometrium, kidney and postmenopausal breast are caused by obesity and physical inactivity [7,8]. Obesity increases the risk of breast cancer by 30% in postmenopausal women and accounts for 21% of all breast cancer deaths, worldwide [9–11]. Obesity is also associated with worse prognosis and poor treatment outcome in cancer [12,13]. In postmenopausal women, estrogen is a major risk factor for breast cancer development. In general, estrogen is synthesized by

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sexual organs, whereas in obese postmenopausal women adipose tissue is the main source of estrogen synthesis [11]. Obesity leads to altered expression of hormones, growth factors, inflammatory cytokines and adipokines which promote cancer cell survival, metastasis, angiogenesis, and decreased cancer cell apoptosis. The detailed molecular mechanisms through which obesity promotes breast cancer development are discussed in the next section. 2. Factors involved in obesity-associated breast cancer and their mechanisms 2.1. Hormones and growth factors Obesity is accompanied by increased estrogen synthesis from adipose-tissue associated stromal cells and elevated levels of insulin and insulin-like growth factors (IGFs) [14–16]. This rise in insulin level is found to be associated with the activation of IGF system and altered levels of IGF binding protein-1 (IGFBP1) and -2 (IGFBP2) which leads to increased bioavailability of IGFs. IGFBPs stabilize and prolong the half life of IGFs and prevent their binding to IGF receptors [17]. IGFBPs also influence the duration of signaling via the IGF receptor by slow release of IGF to its receptor. Further, IGFs lead to macrophage migration and invasion and increased production of pro-inflammatory cytokines by macrophages [18,19]. In chronic hyperinsulinemia, a decreased level of circulating sex-hormone binding globulin (SHBG) leads to increased bio-available estrogen levels which promote mammary tumorigenesis [14]. Insulin, IGFs and insulin like growth factor-1 receptor (IGF-1R) are over expressed in several subtypes of breast cancer [20]. The binding of these ligands to IGF-1R leads to activation of its tyrosine kinase activity [21]. Activation of IGF-1R can promote cell migration and redistribution of E-cadherin and, a- and b-catenins from adherens junctions into the cytoplasm and promote breast tumorigenesis [22]. In addition, IGF-1R leads to activation of PI3K/ Akt and Ras-raf-MAPK signaling which alter the expression of genes involved in cellular proliferation and survival [23]. Overall, this altered hormonal and growth factor profile is associated with increased breast cancer risk. 2.2. Inflammation and inflammatory cytokines Obesity causes subclinical inflammation in both visceral as well as subcutaneous adipose tissue. This inflammation is characterized by necrotic adipocytes surrounded by macrophages which are visualized as crown-like structures (CLS) under light microscope [24–26]. This subclinical inflammation might increases the risk of breast cancer. The adipose tissue-derived factors activate key inflammatory molecules such as nuclear factor kappa-B (NFkB) and signal transducer and activator of transcription-3 (STAT3). Activation of NFkB in adipose tissue further induces the expression of several pro-inflammatory mediators like cyclooxygenase-2 (COX-2), tumor necrosis factor-a (TNF-a), and interleukin-1b (IL-1b), which in turn induces aromatase expression and activity. Activation of these inflammatory mediators leads to altered expression of genes involved in breast carcinogenesis [27–29]. Cytokines, including TNF-a, interleukin-6 (IL-6) and interferons (IFNs) have been reported to be associated with breast cancer development as indicated by their presence within tumor microenvironment and in the tumor metastatic sites [30]. TNFa regulates IL-6 synthesis and the expression of aromatase in adipose tissue [31]. Conditional media from preadipocyte-derived adipocytes was found to increase the proliferation of breast cancer cells, possibly due to the presence of IL-6 from adipocytes [32]. TNF-a treatment in adipocytes drastically decreases the

adiponectin expression and secretion through insulin-like growth factor binding protein-3 (IGFBP-3) and c-Jun N-terminal kinase (JNK) cascades [33,34]. 2.3. Adipokines Adipokines are small peptide hormonal growth factors which are secreted mainly by adipocytes from white adipose tissue. These are the major contributing factors for obesity associated breast cancer [35]. The two most important adipokines which are associated with breast cancer development are leptin and adiponectin. 2.3.1. Leptin Leptin, a multifunctional neuroendocrine peptide hormone, plays a key role in satiety, energy expenditure, food intake, and various reproductive processes [36,37]. Leptin is encoded by obese (ob) gene which is located on chromosome 7, in humans [38]. It consists of 167 amino acids and has a molecular weight of 16 kDa [39]. The molecular actions of leptin are mediated through the cell surface receptors which are members of cytokine family of receptors and are present in various tissues [40]. Six isoforms of leptin receptors ranging from Ob-Ra to Ob-Rf have been identified. Ob-Rb is a long isoform of leptin receptor as it contains a long intracellular domain, comprising of approximately 306 amino acids. The other isoforms (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf) are more abundant in peripheral tissues and contain a short intracellular domain consisting of 23 amino acids [41]. Ob-Re is a soluble leptin receptor, and has been shown to control circulating leptin levels [42]. Adipose tissue is the main source of leptin secretion. In addition, some amount of leptin is also secreted from normal and malignant breast tissue, placenta, stomach and skeletal muscle. The level of leptin increases in proportion to BMI. Serum leptin levels in obese individuals are higher due to its increased release from adipocytes [43]. Leptin could increase or decrease the risk of breast cancer depending on the menopausal status. Plasma leptin level increases the risk of breast cancer in postmenopausal women, whereas its level is inversely related to breast cancer risk in premenopausal women [44]. Leptin and its receptors are over expressed in breast tumors and are associated with distant metastasis [45,46]. Genetically obese leptin-deficient LepobLepob and leptin receptor-deficient LeprdbLeprdb female mice do not develop mammary tumors which provide supporting evidence that leptin and its receptor is involved in breast tumorigenesis [47,48]. The long form of leptin receptor which is mainly expressed in the hypothalamus acts through the activation of JAK2/STAT3 and MAPK pathways, whereas short isoforms activate mainly MAP kinases and appear to be responsible for mitogenic activity [49]. Through activation of JAK2/STAT3 pathway, leptin induces the expression of c-MYC and consequently leads to increased cell survival and proliferation [50]. Another downstream target of JAK/ STAT signaling, cyclin D1 which promotes G1 to S-phase transition during cell cycle progression is found to be increased due to increased JAK/STAT signaling mediated by leptin [51]. Suppressor of cytokine signaling-3 (SOCS3) negatively regulates leptinmediated activation of JAK2/STAT3 signaling by binding to phosphorylated JAK2 proteins [52,53]. Recently, SOCS3 has been reported to down regulate the expression of anti-apoptotic protein survivin through binding with long isoform of leptin receptor (ObRb) and thus inhibiting leptin signaling through JAK/STAT pathway [54]. In a recent study, leptin has been shown to be involved in the regulation of endothelial cell proliferation and in the promotion of angiogenesis [55]. Leptin increases endothelial COX-2 expression

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through p38 MAPK and PI3K/Akt activated mechanisms [56]. In mouse mammary cancer cells, leptin may promote angiogenesis through vascular endothelial growth factor (VEGF) signaling, as leptin treatment results in increased expression of genes for VEGF and VEGF receptor-2 (VEGF-R2) in these cells [57]. Leptin promotes the synthesis of estrogens or conversely reduces follicular estradiol secretion and thus may influence breast cancer risk [58,59]. Leptin exerts its effects by increasing cell viability and proliferation through crosstalk with estrogen receptor-alpha (ERa). The expression of leptin receptor (Ob-R) and its signaling correlates with the presence of ERa in human breast cancer cell lines [60]. Leptin receptor expression was also found to be positively correlated with ERa expression in primary breast carcinoma, which further illustrates the positive association between estrogen and leptin systems in the development of breast cancer in human. In a study on breast cancer patients, the serum leptin level was found to be higher in tamoxifen-treated patients as compared to controls [61,62]. The possible explanation for this is that the binding of tamoxifen reduces the expression of ER which results in concomitant decrease in the leptin receptor expression and ultimately an increased serum leptin level. Leptin induces the functional activation of estrogen receptors in MCF-7 cells via the extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) signal transduction pathway [63]. The antiestrogenic effects of ICI 182,780 on MCF-7 cells have been shown to be ceased by simultaneous treatment with leptin [64]. This study further proved that leptin results in ER activation which neglects the effects of antiestrogenic compound by an unknown mechanism. In a preclinical tumor model for breast cancer, tamoxifen and letrozole did not affect leptin level in the serum [65]. In another study, treatment with exemestane caused 27% decrease in plasma leptin levels following about 3 months of treatment in postmenopausal breast cancer patients [66]. This differential effect might be due to menopausal status or time duration after which plasma leptin level was measured. Leptin can also transactivate HER-2 in breast cancer cells through both the HER-1 and JAK-2 pathways [67]. In a large number of breast tumors, leptin and its receptors are coexpressed with HER-2, which supports the possibility of intratumoral ob-R/HER-2 interactions. The circulating levels of leptin are directly correlated with human telomerase reverse transcriptase (hTERT) expression which is highly expressed in almost all cancer types including breast cancer [68,69]. Thus, leptin is known to be a proliferative, self-renewal and survival factor in obesity-associated breast cancer. Polymorphism of leptin (LEP) and leptin receptor (Ob-R) genes was found to be associated with risk of developing breast cancer in obese women. LEP-2548G/A and LEPR Q223R polymorphisms may be related to obesity as well as enhanced gene expression and increased circulating levels of leptin [70–72]. The presence of LEP2548A/A and LEP-2548G/A in breast cancer cells was found to be associated with high and intermediate leptin mRNA expression, respectively, while cells containing LEP-2548G/G expressed low leptin mRNA levels. The presence of LEP-2548G/A facilitates efficient recruitment of transcription factor specificity protein 1 (Sp1) to leptin promoter DNA under insulin treatment, while Sp1 loading on DNA containing LEP-2548G/G was not insulin-dependent. In contrast, the binding of nucleolin, a transcriptional repressor to LEP-2548G/A was downregulated in response to insulin, while it was not regulated on LEP-2548G/G [73]. Thus, the presence of LEP-2548G/A might enhance leptin expression in breast cancer cells via Sp1- and nucleolin-dependent mechanisms and this enhanced leptin expression is associated with breast cancer risk. In a case–control study, a modest increase in risk of developing breast cancer was found to be associated with LEP2548A/A genotype compared to the LEP-2548G/G genotype and the

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association was stronger among the postmenopausal women who were obese [74]. 2.3.2. Adiponectin Another adipokine involved in obesity-associated breast cancer is adiponectin, which is mainly secreted by adipocytes and some amount is also secreted by other types of cells [75,76]. It has a molecular weight of 28–30 kDa. Several isoforms of adiponectin have been identified. Amongst them, full length adiponectin known as Acrp30 and globular adiponectin known as gAcrp30 are important because of their strong and identified affinity with adiponectin receptors [77]. There are mainly two adiponectin receptors (AdipoRs), AdipoR1 and AdipoR2. Of these, AdipoR1 has high affinity for gAcrp30 and AdipoR2 is the intermediate affinity receptor for gAcrp30 and Acrp30 [75,78]. The altered expression of adiponectin receptors have been reported in most of the breast cancer cell lines such as MDA-MB-231, MCF-7, T47D and SK-BR-3. The variation is found in the expression levels of AdipoR1 and AdipoR2 in breast cancer cell lines. MDA-MB-231, T47D, and MCF7 cells showed higher expression of AdipoR1 and lower expression of AdipoR2, whereas MDA-MB-361 cells showed higher expression of AdipoR2 [79–81]. Several retrospective and prospective case–control studies have proved the association of low serum adiponectin levels with increased risk of breast cancer. There is a controversy on whether low adiponectin level increases the risk of breast cancer among both premenopausal and postmenopausal women or it is associated with increased risk only in postmenopausal women. Some studies have reported that there is a well defined inverse association between adiponectin and breast cancer risk in both pre- and post-menopausal women. In contrast, some other studies have reported that lower adiponectin levels are associated with breast cancer risk only in postmenopausal women [82–87]. These differences might be due to female sex hormones especially the estrogens since serum adiponectin concentration is inversely correlated with serum estradiol concentration in postmenopausal women but not in premenopausal women [88]. Addition of full length adiponectin, i.e. Acrp30 to ER-positive cell lines (MCF-7, T47D, and MDA-MB-361) results in increased apoptosis by increased poly (ADP-ribose) polymerase (PARP) cleavage. Increase in cleaved caspase-8 on adiponectin treatment was also found in MDA-MB-231 and MCF-7 cells leading to apoptosis. The treatment of MDA-ERa7 cell line (produced by transfection of ERa gene into MDA-MB-231 cell line) with truncated form of adiponectin, i.e. gAcrp30 reduces its growth probably by decreasing phosphorylation of JNK2 [79]. This study shows that ER expression is important for signaling through adiponectin receptors and consequently cell growth inhibition by adiponectin treatment. Estrogen has been found to suppress adiponectin expression in 3T3-L1 adipocyte cell line [89]. This suggests that estrogen might be an important factor in obesityinduced breast carcinogenesis through decreased adiponectin expression in adipocytes of adipose tissue. The anti-proliferative and pro-apoptotic effects of adiponectin might be mediated by its binding to AdipoRs, and concomitant activation of AMP-activated protein kinase (AMPK), and the inactivation of p42/p44 MAPK [90]. Adiponectin mediated activation of AMPK is involved in anti-breast cancer activities through regulation of PI3K/Akt pathway [91]. In MDA-MB-231 cells, adiponectin-activated AMPK reduces cell invasion by inducing AKT dephosphorylation through protein phosphatase-2 activity [92]. Adiponectin may also mediate its effects by regulating the expression of different tumor suppressor genes, oncogenes, proand anti-apoptotic genes, and cell cycle regulatory genes including p53, Bax, Bcl-2, c-myc, cyclin D1, MAPK3 and ataxia telangiectasia mutated (ATM) [80,90]. Adiponectin significantly inhibits the cell

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proliferation induced by leptin, oxidized low-density lipoprotein (LDL) and several other growth factors like platelet-derived growth factor subunit B homodimer (PDGF-BB), basic fibroblast growth factor (bFGF), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) [93–95]. Adiponectin inhibits the seruminduced phosphorylation of AKT and glycogen synthase kinase-3b (GSK-3b) and suppresses the intracellular accumulation of bcatenin in MDA-MB-231 and T47D breast cancer cell lines. This shows that GSK-3b/b-catenin signaling pathway is involved in adiponectin-mediated growth inhibition in breast cancer cell lines [95]. Thus, adiponectin acts as anti-proliferative, pro-apoptotic and inhibitor of angiogenesis in breast cancer. Fig. 1 summarizes the main signaling pathways mediated by estrogen, leptin and adiponectin which are involved in the process of breast carcinogenesis. 2.4. Tumor microenvironment The tumor microenvironment comprises of cells, soluble factors, signaling molecules, and extracellular matrix that can promote tumorigenesis, and resist the tumor from host immunity and therapeutic response. Obesity reduces the oxygen level in the tumor microenvironment leading to hypoxic condition [97]. Hypoxia in the peri-tumoral fat is reported to promote tumor site hypoxia. The up regulation of hypoxia-inducible factor-a (HIF1a) takes place in the hypoxic state which leads to altered expression of several genes involved in angiogenesis, cell proliferation and apoptosis which ultimately results in cellular

adaptation to low oxygen concentration [98]. In the adipose tissue, hypoxia induces the secretion of pro-angiogenic and inflammatory cytokines [99,100]. Hypoxia down regulates the expression of CCAAT/enhancer binding protein-a (C/EBPa) in T-47D breast cancer cells through binding of HIF-1a to C/EBPa promoter site [101]. C/EBPa is a transcription factor which induces apoptosis, inhibits cell proliferation and involved in cellular differentiation [102]. 3. Current clinical strategies and trials on obesity-associated breast cancer 3.1. Hormones- and growth factors-targeted Despite the significant heterogeneity, several advances have been made over the past decade for the care of patients with breast cancer. Available treatments for breast cancer include chemotherapy, radiotherapy, hormonal and targeted therapy. Anthracyclines (e.g. doxorubicin) and taxanes (e.g. docetaxel) are two most commonly used chemotherapeutic agents for the treatment of breast cancer. These days, targeted and hormonal therapies are showing promising results in the prognosis of breast cancer. Agents used in targeted therapy include inhibitors of receptor tyrosine kinases (epidermal growth factor family inhibitors, e.g. gefitinib and erlotinib) and nonreceptor tyrosine kinases, inhibitors of intracellular signaling pathways such as PI3K/Akt and RasRaf MAPK, angiogenesis inhibitors, agents that interfere with DNA repair (e.g. PARP inhibitors), and hormonal antagonists. The use of

Fig. 1. Estrogen, leptin and adiponectin signaling in breast carcinogenesis. The signaling through three major players involved in obesity-associated breast cancer (estrogen, leptin and adiponectin) is shown here. Estrogen binding to estrogen receptor-a (ERa) in the cytoplasm leads to ERa dimerization. This dimerized ERa passes through the nucleus and binds to estrogen responsive elements (EREs) at the promoter region of some tumor promoting genes and leads to their expression. The high level of leptin in the adipose tissue is directly correlated with the breast cancer progression. Leptin binds to its cell surface receptor and leads to activation of several oncogenic pathways such as JAK2/STAT3 pathway, PI3K/AKT pathway, and MAPK pathway (here we shown only JAK2/STAT3 pathway, the major pathway activated by leptin). The phosphorylated JAK2 binds to cytoplasmic domains of leptin receptor and causes their phosphorylation which ultimately leads to phosphorylation of STAT3. The dimerization of STAT3 takes place and the dimerized STAT3 binds at the promoter region of some tumor promoting genes (e.g. c-myc, EGFR, and src), cell cycle promoting genes (e.g. Cyclin D1) or anti-apoptotic genes (e.g. survivin) and leads to their expression. Leptin has its actions not only through leptin receptor but it also has crosstalk signaling with estrogen receptor-a. Leptin increases the expression of aromatase and thus causes increased estrogen synthesis. In the absence of estrogen, leptin also stimulates signaling through ERa through MAPKdependent pathway [96]. The low level of adiponectin results in abrogated adiponectin signaling through activation of MAPK pathway and inhibition of AMPK pathway. The end result of all of these signaling pathways is increased cell proliferation and survival and/or decreased apoptosis and ultimately the induction of breast cancer.

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targeted therapies such as estrogen antagonist (e.g. tamoxifen and fulvestrant) in estrogen receptor (ER) positive cases and of monoclonal antibody trastazumab (Herceptin) for the inhibition of signaling through HER-2 receptor have contributed significantly to these advances [103]. Mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus) which target mTOR pathway is a newly added targeted therapy in breast cancer treatment [104]. Combination therapy has proven to be more effective approach than the mono-agent therapy for breast cancer treatment. Targeting HER-2 with trastazumab and VEGF with bevacizumab in combination with chemotherapy is more effective than single agent in the treatment of breast cancer [105]. The combination of aromatase inhibitor (letrozole) and HER-2 inhibitor (trastazumab) is an effective therapy in hormonal-refractory breast cancer due to the fact that the signaling through HER-2 increases in aromatase inhibitor resistant breast tumors [106,107]. Lapatinib, a dualEGFR/HER-2 selective reversible inhibitor in combination with trastazumab significantly improved the progression-free survival (PFS) in HER-2 over expressing breast cancer cells [105]. Thus, this combination of lapatinib and trastazumab can be effective in the treatment of trastazumab-refractory metastatic breast cancer. Reducing estrogen synthesis by targeting aromatase or inhibiting signaling through estrogen receptor could be a therapeutic option in obesity-associated breast cancer. The aromatase inhibitors inhibit the estrogen synthesis and antiestrogens inhibit and/or degrade estrogen receptor and consequently abrogate oncogenic signaling. Therefore, these two classes of compounds may be effective for treating obesity-related breast cancer. Tamoxifen shown to reduce serum IGF-I levels in obese women. Aromatase inhibitors such as letrozole reduce plasma estrogen levels in obese postmenopausal women [108]. Thus, these antiestrogens could be used to treat obesity-related breast cancer as the levels of both IGF-I and estrogen were found to be increased in obesity-associated breast cancer. Roscovitine is a selective cyclin-dependent kinase (CDK) inhibitor which has found to reduce estrogen-induced phosphorylation of ERa at Ser118 in MCF-7 cells and thus inhibited signaling through ERa [109]. The inhibition of signaling through JAK-2/STAT3 pathway by inhibiting STAT3 or its upstream kinases may also be beneficial. Agents that could inhibit signaling through the insulin receptor might be potential therapeutics in reducing insulin-mediated tumor growth. FDA approved drugs such as phentermine, diethylpropion, phendimetrazine, orlistat and lorcaserin which are used in the treatment of hyperlipidemia/hypercholesterolemia and obesity can also be effective candidates for the treatment of obesityrelated breast malignancies. Pitavastatin, a drug used for the treatment of hyperlipidemia significantly reduced the development of diethylnitrosamine (DEN)-induced liver carcinogenesis in

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db/db-obese mice. Orlistat has been found to inhibit growth of breast cancer cells through blockade of cell cycle progression, promotion of apoptosis, and repression of HER-2/neu [110,111]. The therapeutic agents for the treatment of obesity-associated breast cancer targeting hormones and growth factors are listed in Table 1. Dietary and physical interventions such as reduction in high-fat diet and increased physical activity can reduce the risk of breast cancer in postmenopausal women. A balanced energy budget of body controlled by limitation of calorie intake and/or by elevation of energy expenditure could be key ways to reduce obesity [115]. The activation of AMPK by bioactive food components may be an important strategy for the prevention of several cancers caused due to increased BMI. AMPK plays an important role in cellular energy homeostasis through the stimulation of fatty acid oxidation, inhibition of lipogenesis and modulation of insulin secretion by pancreatic beta-cells [116]. Thus, the phytochemicals that activate AMPK may also be useful in reducing the risk of obesitymediated breast cancer in postmenopausal women. 3.2. Adipokines- and cytokines-targeted Inflammatory cytokines and adipokines are potent targets for the treatment of obesity-associated breast malignancy. An important strategy for the treatment of this class of cancer is the development of pharmacological compounds that target obesity-related pathways. There are various compounds that are being tested in clinical trials for obesity [117]. These compounds can also be useful to treat obesity-associated breast tumorigenesis possibly in combination with anti-breast cancer agents. Fig. 2 illustrates the various therapeutic agents and their targets in obesity and obesity-associated carcinogenesis. The antagonists of leptin that can inhibit signaling through the leptin receptor and, adiponectin agonists that can mimic the action of adiponectin could also be used to inhibit the growth of epithelial breast cells. Pegylated leptin peptide receptor antagonist 2 (PEGLPrA2) reduced the growth of breast cancer cells particularly ERpositive cells in xenograft mice model by reducing the expression of pro-angiogenic (e.g. VEGF/VEGFR-2) and pro-proliferative (e.g. proliferating cell nuclear antigen and cyclin D1) molecules [118]. ADP-355 is a peptide-based adiponectin receptor agonist which shows growth inhibitory effects on breast cancer cell lines as well as on orthotopic xenograft breast cancer model [119]. Metformin, an anti-diabetic drug was found to reduce IL-6 mRNA expression level and to enhance mRNA expression level of IL-1R, the receptor for a naturally occurring anti-inflammatory cytokine. Action of metformin may be attributable to be mediated through the activation of AMPK pathway as silencing of AMPK-a1 results in lipopolysaccharide (LPS)-induced IL-6 and

Table 1 Therapeutic agents in targeting hormones and growth factors for breast cancer treatment. Drug class

Drug name

Mode of action

Status

References

Aromatase inhibitors

Letrozole, anastrozole, exemestane

Clinical phase III (with or without chemotherapy) for invasive breast cancer in postmenopausal women

[112]

Antiestrogens and estrogen antagonists

Tamoxifen, fulvestrant

Act through the inhibition of aromatase, an enzyme which catalyze the synthesis of estrogen from its precursor hormones Tamoxifen mainly acts through inhibition of ER. Fulvestrant mainly acts through ER degradation.

[113,114]

CDK-inhibitors

Roscovitine

Tamoxifen is in clinical phase I/II for triple negative breast cancer (in combination with decitabine and LBH589) Fulvestrant is in Clinical phase III (for postmenopausal breast cancer) Preclinical

Anti-obesity and anti-hyperlipidemia drugs

Orlistat, Pitavastatin

Preclinical

[111,112]

Reduces phosphorylation of ERa, thereby inhibits downstream signaling Orlistat acts through blockade of cell cycle progression, promotion of apoptosis, and repression of HER2/neu

[108]

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Fig. 2. Schematic diagram illustrating therapeutic agents targeting different signaling molecules involved in obesity and obesity-associated breast cancer. In obesity, the activity of aromatase enzyme increases which leads to increased production of estrogen (E2) by the adipose tissue. Estrogen signaling activates several downstream genes such as cyclin D1 and c-myc. Aromatase inhibitors and antiestrogens can be used to target this pathway in obesity-associated breast cancer. Obesity also causes chronic inflammation which leads to an increased expression and secretion of several inflammatory molecules such as TNF-a and IL-6. TNF-a promotes downstream NFkB pathway in which NFkB binds to its response elements in the nucleus and increases the expression of its target genes. TNF-a further enhances IL-6 expression, IL-6 activates JAK2/ STAT3 signaling which leads to the expression of STAT3 target genes. In obesity, Wnt/b-catenin signaling leads to the activation of b-catenin target genes involved in breast carcinogenesis. The activation of these oncogenic pathways through obesity-inflammation axis finally leads to breast carcinogenesis. Increased adiponectin activity activates AMPK which causes fatty acid oxidation and leads to adipose tissue reduction. The therapeutic agents targeting these molecules are depicted in the figure. Abbreviations: E2, estrogen; ER, estrogen receptor; ERE, estrogen response element; RE, response element; FASN, fatty acid synthase; PM, plasma membrane; Adn, adiponectin.

IL-8 expression [32]. Preclinical studies have demonstrated that metformin can inhibit the growth of breast cancer cells. Metformin mainly acts through the inhibition of signaling by mTOR pathway and leads to reduced expression of HER-2 protein on breast cancer cells [31]. Thus, metformin may also show promising results in the treatment of obesity-related breast cancer.

Anti-inflammatory drugs which act through the inhibition of key inflammatory molecules such as IL-6, TNF-a and COX-2 can also be used for treating obesity-associated breast cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin could prevent the occurrence of cancers of epithelial origin including breast cancer as evidenced by in vitro, in vivo and epidemiological studies. Aspirin has been found to promote apoptotic pathways in

Table 2 Synthetic molecules in targeting adipokines and inflammatory cytokines involved in obesity-associated breast cancer. Name of the compound

Category

Mode of action

Target/pathway

Status

Refs.

Pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) ADP-355

Synthetic peptide

Leptin

Preclinical

[118]

Adiponectin

Preclinical

[119]

Aspirin

Synthetic

COX-1 and COX-2

Preclinical

[31]

Celecoxib Exemestane in combination with celecoxib Infliximab Metformin

Synthetic Synthetic

Reduces the expression of proangiogenic and pro-proliferative factors Mimics the action of adiponectin by modulating key signaling pathways in an adiponectin-like manner Anti-inflammatory acts through upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins, Anti-inflammatory Aromatase inhibitor with COX-2 inhibitor Anti-inflammatory Acts through either reduced expression of pro-inflammatory cytokines and/or activation of AMPK pathway, inhibition of mTOR pathway, lowering IGF-1 levels

COX2 Aromatase And COX-2

Phase II completed Phase II completed

[120] [122]

TNF-a AMPK, IGF-1, mTOR

Phase II completed Preclinical

[123] [31,32]

Synthetic peptide

Monoclonal antibody Synthetic

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Table 3 Phytochemicals in targeting adipokines and inflammatory cytokines involved in obesity-associated breast cancer. Name of the compound

Category

Mode of action

Target/pathway

Status

Refs.

Curcumin (-)-Catechin EGCG

Polyphenol Flavanol Flavanol

NFkB, and COX-2, PPARg Adiponectin AMPK, pancreatic lipases

Preclinical Preclinical Preclinical

[129] [146,147] [143,144]

Genistein Isoquercitrin Myricetin

Isoflavonoid Flavones Flavones

Anti-inflammatory, fatty acid oxidation Increases expression of adiponectin Promotes fat oxidation and inhibit adipocyte differentiation, decreases fat absorption Inhibitor of adipocyte differentiation Prevents preadipocyte differentiation into adipocyte Inhibits lipid droplet accumulation in adipocytes

Preclinical Preclinical Preclinical

[139–141] [148,149] [150]

Quercetin Resveratrol Ursolic acid

Flavone Polyphenol Triterpenoid

Anti-inflammatory, inhibits adipocyte cell growth Anti-inflammatory, inhibits adipocyte differentiation Anti-inflammatory

AMPK, Fatty acid synthase Wnt/b-catenin Peroxisome proliferator-activated receptor-a (PPARa) COX-2, NFkB and TNF-a IL-6, TNF-a and NFkB, AMPK, PPARg NFkB, and COX-2

Phase I Preclinical Preclinical

[136] [131] [127,137,138]

cancer cell lines by up regulation of pro-apoptotic and down regulation of anti-apoptotic proteins [31]. There are several other drugs in clinical trials for the treatment of obesity and/or obesity associated breast cancer targeting cytokines and inflammatory mediators, which are further listed in Table 2. Celecoxib, a COX-2 inhibitor successfully completed phase II clinical trial for the treatment of postmenopausal breast cancer [120]. Exemestane, an aromatase inhibitor in combination with avandamet (combination of rosiglitazone and metformin) was found to be effective in phase I clinical trial to treat breast cancer in obese postmenopausal women [121]. The combination of Exemestane and Celecoxib was tested in phase II clinical trial for the treatment of breast cancer in obese postmenopausal women and found to be effective [122]. Infliximab, a monoclonal antibody targeting TNF-a completed phase II clinical trial for the treatment of cancer related fatigue in patients who had undergone breast cancer treatment [123]. In a pilot study, docosahexaenoic acid (DHA), an omega-3 fatty acid, reduced inflammation and aromatase expression in obese postmenopausal women [124]. Further clinical studies on the efficacy of DHA against breast cancer are currently ongoing. Green tea extract is being tested in phase II clinical trial in healthy postmenopausal women [125]. (-)-Catechin, one of the components of green tea is in phase I clinical trial for treating women with hormone receptor-negative stages I–III breast cancer [126]. The efficacy of these drugs could also be tested in obesity-associated breast cancer possibly in combination with anti-breast cancer drugs. Phytochemicals found in fruits, vegetables have also shown their efficacy against obesity and obesity-associated cancers. Curcumin, phytochemical found in turmeric, is an anti-inflammatory agent and shown to modulates NFkB, Stat3, COX-2, Akt, and mTOR pathways [127,128]. By targeting these obesity-related pathways, curcumin reduces the symptoms of obesity such as hyperglycemia and hyperlipidemia and thus inhibits obesityassociated tumor growth [129,130]. Resveratrol, a dietary polyphenol generally found in grapes, shown to inhibit inflammatory cytokines and chemokines [131–133]. Quercetin generally found in citrus fruits, onions, tea and red wine possesses antiinflammatory and anti-oxidant activities. It alters Akt/mTOR pathway, COX-2 expression, NFkB signaling, TNF-a expression, and VEGF expression [134,135]. A phase I clinical study showed that quercetin inhibits tumor growth and inflammation [136]. Ursolic acid is a triterpenoid found in rose-mary, shown to be antiinflammatory and insulin sensitizing in nature [127,137]. Ursolic acid also inhibits VEGF and other inflammatory growth factors in mice, thus it could also be an anti-angiogenic agent [138]. Hence, these anti-inflammatory and anti-angiogenic phytochemicals could be designed to test their efficacy either alone or in combination with available therapeutic agents against obesityassociated breast cancer.

Dietary flavonoids such as genistein and ()-catechin exerts anti-obesity effects either by promoting fatty acid oxidation or by inhibiting adipocyte differentiation [139–147]. Genistein is found in soy (Glycine max) and soy food products. Genistein inhibits adipocyte differentiation probably by promoting AMPK-activation [139,140]. Genistein was also found to inhibit fatty acid synthase expression and JAK2 phosphorylation which indirectly leads to suppression of adipocyte differentiation [141]. EGCG and ()catechin are components of green tea and known as green tea polyphenols. EGCG was reported to have pancreatic lipase inhibitory activity and was also found to inhibit adipocyte differentiation by AMPK-activation [142–145]. Similar to EGCG, (-)-catechin also activates AMPK and inhibits adipocyte differentiation. In addition to this, (-)-catechin also increases the expression of adiponectin [146,147]. Isoquercitrin and myricetin are flavones that also exert anti-obesity effects. Isoquercitrin activates wnt/bcatenin signaling, thus inhibits preadipocyte differentiation into adipocytes [148,149]. Myricetin activates PPARa and inhibits lipid deposition in adipocytes [150]. Phytochemicals with different phases of their preclinical and clinical development against obesity and obesity-associated breast cancer are further listed in Table 3. 4. Future directions and perspectives The saying ‘‘Prevention is better than cure’’ needs to be followed to reduce the number of obesity-associated breast cancer cases. Reduction of high calories in diet by reducing the consumption of fat-rich diet and increased physical activity are the two most important prevention strategies for obesity and ultimately for obesity-associated breast cancer. Development of more effective drugs that can selectively inhibit the estrogen synthesis with minimal side effects might be useful candidates against obesityassociated breast cancer. More research needs to be focused on the development of effective leptin antagonists and adiponectin agonists. Therapeutic agents that can reduce energy metabolism and induce adipocyte degeneration might also prove to be effective candidate drugs. Combination of chemotherapy and hormonal therapy or different hormonal therapies is to be tested in the clinical trials. Future research on the efficacy of anti-obesity drugs such as pitavastatin and orlistat in the treatment of obesity-related mammary carcinogenesis is also needed. The efficacy of antidiabetic drug metformin against breast cancer needs to be tested in clinical trials as it has shown its efficacy in preclinical trials. More research is also needed on the efficacy of anti-inflammatory drugs against obesity-associated breast cancer. 5. Conclusion Obesity is a strong risk factor for the increased breast cancer incidence and mortality in postmenopausal women. The detailed

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molecular mechanisms involved in obesity-associated breast cancer need to be studied. However, the known signaling pathways involved in obesity-associated breast cancer are mediated through estrogen, insulin, leptin, adiponectin and inflammatory cytokines. In fat cells, increased aromatase activity leads to an increase in estrogen synthesis which further decreases the level of SHBG, both causally linked with obesity-associated breast cancer. The levels of Insulin and insulin like growth factors are increased in obesity which increases the growth rate of cancer cells via activation of key tumorigenic pathways such as PI3K/Akt/mTOR and Ras/Raf/MAPK. The increased leptin and/or decreased adiponectin levels are the strong risk factors for the development of postmenopausal breast cancer. Obesity-inflammation axis plays an important role in the development of breast cancer. In obese condition, increased production of inflammatory cytokines has been found which are potentially linked to breast cancer development via several mechanisms including cellular proliferation and genetic damage. The therapeutic regimens for obesity-associated breast cancer include aromatase inhibitors, estrogen antagonists, leptin antagonists, adiponectin agonists, and anti-inflammatory drugs. However their trial and use is warranted with clinical significance. Acknowledgements This work was supported by the EpiHeD-Network Scheme (BSC0118) and Research fellowship grants (SK, SS) from the Council of Scientific and Industrial Research (CSIR), Government of India, India. Part of this work was also supported by grants to S.M.M. from the Science & Engineering Research Board (SERB), New Delhi, India. We thank Ms. Isha Soni for her assistance in proofreading the manuscript. CSIR-CDRI communication Number-8554. No conflict of interest. References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. [2] Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas 2001;38:103–13. discussion 13–6. [3] Key J, Hodgson S, Omar RZ, Jensen TK, Thompson SG, Boobis AR, et al. Metaanalysis of studies of alcohol and breast cancer with consideration of the methodological issues. Cancer Causes Control 2006;17:759–70. [4] Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007;8:292–3. [5] Donohoe CL, Doyle SL, Reynolds JV. Visceral adiposity, insulin resistance and cancer risk. Diabetol Metab Syndr 2011;3:12. [6] Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011;2011:197636. [7] Vainio H, Kaaks R, Bianchini F. Weight control and physical activity in cancer prevention: international evaluation of the evidence. Eur J Cancer Prev 2002;11(Suppl. 2):S94–100. [8] Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569–78. [9] Rack B, Andergassen U, Neugebauer J, Salmen J, Hepp P, Sommer H, et al. The German SUCCESS C Study – The First European Lifestyle Study on breast cancer. Breast Care (Basel) 2010;5:395–400. [10] Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M. (Cancers) CRAcg. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005;366:1784–93. [11] Carmichael AR. Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 2006;113:1160–6. [12] Abrahamson PE, Gammon MD, Lund MJ, Flagg EW, Porter PL, Stevens J, et al. General and abdominal obesity and survival among young women with breast cancer. Cancer Epidemiol Biomarkers Prev 2006;15:1871–7. [13] Porter GA, Inglis KM, Wood LA, Veugelers PJ. Effect of obesity on presentation of breast cancer. Ann Surg Oncol 2006;13:327–32. [14] Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004;23:6365–78. [15] Maccio` A, Madeddu C, Mantovani G. Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives. Obes Rev 2009;10:660–70. [16] Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010;61:301–16. [17] Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3–34.

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Inhibition of adipogenesis by Wnt signaling. Science 2000;289:950–3. [149] Lee SH, Kim B, Oh MJ, Yoon J, Kim HY, Lee KJ, et al. Persicaria hydropiper (L.) spach and its flavonoid components, isoquercitrin and isorhamnetin, activate the Wnt/b-catenin pathway and inhibit adipocyte differentiation of 3T3-L1 cells. Phytother Res 2011;25:1629–35. [150] Chang CJ, Tzeng TF, Liou SS, Chang YS, Liu IM. Myricetin increases hepatic peroxisome proliferator-activated receptor a protein expression and decreases plasma lipids and adiposity in rats. Evid Based Complement Alternat Med 2012;2012:787152. Syed Musthapa Meeran Ph.D is currently a senior scientist at the Division of Endocrinology of CSIR-Central Drug Research Institute. In his doctoral work, he studied the role of asbestos and other biomass pollutants-mediated genetic and cytogentic changes in the pulmonary system. To further in his postdoctoral study, he evaluated the role of inflammatory cytokines for the skin cancer risk at the Department of Dermatology, University of Alabama at Birmingham. Later he became a faculty at the Department of Biology, University of Alabama at Birmingham, where he studied the epigenetic and chemoprevention of breast cancer. He is currently working on the novel genetic and epigenetic targets for breast and lung cancer prevention as well as therapy with bioactive dietary supplements. His research interest are also focused on the role of various cytokine and chemokine mediated intra cellular signaling in the cancer progression, especially breast cancer. Sajid Khan obtained his Masters degree in Biotechnology from Aligarh Muslim University, Aligarh, India in 2011. Currently, he is working as a doctoral research fellow under the guidance of Dr. Syed Musthapa Meeran in the Endocrinology Division of CSIR-Central Drug Research Institute, Lucknow, India. His research work is primarily focused on the role of leptin and adiponectin in obesity-associated breast cancer. He also obtained Senior Research Fellowship (CSIR-SRF) from the Council of Scientific and Industrial Research, New Delhi, India for his doctoral study.

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513 Samriddhi Shukla has received her Masters degree in Biotechnology from Dr. R.M.L. Avadh University, Faizabad, India with university ranking and gold medal. She is currently pursuing her doctoral research under the mentorship of Dr. Syed Musthapa Meeran, CSIR-Central Drug Research Institute, Lucknow, India. Her research work mainly focuses on the genetics and epigenetics of lung cancer. She also obtained Senior Research Fellowship (CSIR-SRF) from the Council of Scientific and Industrial Research, New Delhi, India for her doctoral research work.

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Sonam Sinha earned her Masters in Biotechnology from AMITY University, Lucknow, India in 2011. She is currently engaged as a Project Assistant under the supervision of Dr. Syed Musthapa Meeran at CSIR-Central Drug Research Institute, Lucknow, India. Her research interest is mainly focused on studying novel genetic and epigenetic targets for breast cancer prevention and therapy with bioactive dietary supplements.