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

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

Article history:

Available online 21 October 2013

Keywords:

Obesity

Breast cancer

Leptin

Adiponectin

Cytokines

A B S T R A C T

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.

� 2013 Elsevier Ltd. All rights reserved.

Contents lists available at ScienceDirect

Cytokine & Growth Factor Reviews

jo ur n al ho mep ag e: www .e lsev ier . c om / loc ate /c yto g f r

1. Introduction

Breast cancer is the most common type of cancer and also theleading 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, insulin-

like 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, heparin-

binding 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; PEG-

LPrA2, pegylated leptin peptide receptor antagonist 2; mTOR, mammalian target of

rapamycin; EGCG, epigallocatechin-3-gallate; NSAIDs, non-steroidal anti-inflam-

matory 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: s.musthapa@cdri.res.in, syedmusthapa@gmail.com

(S.M. Meeran).

1359-6101/$ – see front matter � 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) oftotal cancer-related deaths in the year 2008 [1]. Severalreproductive and lifestyle factors are associated with thedevelopment of breast cancer. Among the reproductive factorsare long menstrual history, nulliparity, increased use of oralcontraceptives, and giving birth to a child at later age [2]. Lifestylefactors including less physical activity, consumption of high caloriediets, cigarette smoking and alcohol consumption are stronglyassociated with increased risk of breast cancer development [3,4].

Obesity is an abnormal or excessive fat accumulation in adiposetissue which leads to impaired health [5]. According to WorldHealth Organization (WHO), obesity is defined as having a bodymass index (BMI) of equal to or higher than 30 kg/m2. It is themajor cause of onset of a number of diseases such as type-2diabetes, cardiovascular diseases (CVDs), infertility, and severaltypes of cancers [6]. It is estimated that 25–30% of cancers atnumerous sites such as esophagus, pancreas, colorectum, endo-metrium, kidney and postmenopausal breast are caused by obesityand physical inactivity [7,8]. Obesity increases the risk of breastcancer by 30% in postmenopausal women and accounts for 21% ofall breast cancer deaths, worldwide [9–11]. Obesity is alsoassociated with worse prognosis and poor treatment outcome incancer [12,13].

In postmenopausal women, estrogen is a major risk factor forbreast cancer development. In general, estrogen is synthesized by

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513504

sexual organs, whereas in obese postmenopausal women adiposetissue is the main source of estrogen synthesis [11]. Obesity leadsto altered expression of hormones, growth factors, inflammatorycytokines and adipokines which promote cancer cell survival,metastasis, angiogenesis, and decreased cancer cell apoptosis. Thedetailed molecular mechanisms through which obesity promotesbreast cancer development are discussed in the next section.

2. Factors involved in obesity-associated breast cancer andtheir mechanisms

2.1. Hormones and growth factors

Obesity is accompanied by increased estrogen synthesis fromadipose-tissue associated stromal cells and elevated levels ofinsulin and insulin-like growth factors (IGFs) [14–16]. This rise ininsulin level is found to be associated with the activation of IGFsystem and altered levels of IGF binding protein-1 (IGFBP1) and -2(IGFBP2) which leads to increased bioavailability of IGFs. IGFBPsstabilize and prolong the half life of IGFs and prevent their bindingto IGF receptors [17]. IGFBPs also influence the duration ofsignaling via the IGF receptor by slow release of IGF to its receptor.Further, IGFs lead to macrophage migration and invasion andincreased production of pro-inflammatory cytokines by macro-phages [18,19]. In chronic hyperinsulinemia, a decreased level ofcirculating sex-hormone binding globulin (SHBG) leads toincreased bio-available estrogen levels which promote mammarytumorigenesis [14].

Insulin, IGFs and insulin like growth factor-1 receptor (IGF-1R)are over expressed in several subtypes of breast cancer [20]. Thebinding of these ligands to IGF-1R leads to activation of its tyrosinekinase activity [21]. Activation of IGF-1R can promote cellmigration and redistribution of E-cadherin and, a- and b-cateninsfrom adherens junctions into the cytoplasm and promote breasttumorigenesis [22]. In addition, IGF-1R leads to activation of PI3K/Akt and Ras-raf-MAPK signaling which alter the expression ofgenes involved in cellular proliferation and survival [23]. Overall,this altered hormonal and growth factor profile is associated withincreased breast cancer risk.

2.2. Inflammation and inflammatory cytokines

Obesity causes subclinical inflammation in both visceral as wellas subcutaneous adipose tissue. This inflammation is characterizedby necrotic adipocytes surrounded by macrophages which arevisualized as crown-like structures (CLS) under light microscope[24–26]. This subclinical inflammation might increases the risk ofbreast cancer.

The adipose tissue-derived factors activate key inflammatorymolecules such as nuclear factor kappa-B (NFkB) and signaltransducer and activator of transcription-3 (STAT3). Activation ofNFkB in adipose tissue further induces the expression of severalpro-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 alteredexpression 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 cancerdevelopment as indicated by their presence within tumormicroenvironment and in the tumor metastatic sites [30]. TNF-a regulates IL-6 synthesis and the expression of aromatase inadipose tissue [31]. Conditional media from preadipocyte-derivedadipocytes was found to increase the proliferation of breastcancer 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 growthfactor 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 whichare secreted mainly by adipocytes from white adipose tissue. Theseare the major contributing factors for obesity associated breastcancer [35]. The two most important adipokines which areassociated with breast cancer development are leptin andadiponectin.

2.3.1. Leptin

Leptin, a multifunctional neuroendocrine peptide hormone,plays a key role in satiety, energy expenditure, food intake, andvarious reproductive processes [36,37]. Leptin is encoded by obese

(ob) gene which is located on chromosome 7, in humans [38]. Itconsists of 167 amino acids and has a molecular weight of 16 kDa[39]. The molecular actions of leptin are mediated through the cellsurface receptors which are members of cytokine family ofreceptors and are present in various tissues [40]. Six isoforms ofleptin receptors ranging from Ob-Ra to Ob-Rf have been identified.Ob-Rb is a long isoform of leptin receptor as it contains a longintracellular domain, comprising of approximately 306 aminoacids. The other isoforms (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf) aremore abundant in peripheral tissues and contain a shortintracellular domain consisting of 23 amino acids [41]. Ob-Re isa soluble leptin receptor, and has been shown to control circulatingleptin levels [42].

Adipose tissue is the main source of leptin secretion. Inaddition, some amount of leptin is also secreted from normal andmalignant breast tissue, placenta, stomach and skeletal muscle.The level of leptin increases in proportion to BMI. Serum leptinlevels in obese individuals are higher due to its increased releasefrom adipocytes [43]. Leptin could increase or decrease the risk ofbreast cancer depending on the menopausal status. Plasma leptinlevel increases the risk of breast cancer in postmenopausal women,whereas its level is inversely related to breast cancer risk inpremenopausal women [44]. Leptin and its receptors are overexpressed in breast tumors and are associated with distantmetastasis [45,46]. Genetically obese leptin-deficient LepobLepob

and leptin receptor-deficient LeprdbLeprdb female mice do notdevelop mammary tumors which provide supporting evidencethat leptin and its receptor is involved in breast tumorigenesis[47,48].

The long form of leptin receptor which is mainly expressed inthe hypothalamus acts through the activation of JAK2/STAT3 andMAPK pathways, whereas short isoforms activate mainly MAPkinases and appear to be responsible for mitogenic activity [49].Through activation of JAK2/STAT3 pathway, leptin induces theexpression of c-MYC and consequently leads to increased cellsurvival and proliferation [50]. Another downstream target of JAK/STAT signaling, cyclin D1 which promotes G1 to S-phase transitionduring cell cycle progression is found to be increased due toincreased JAK/STAT signaling mediated by leptin [51]. Suppressorof cytokine signaling-3 (SOCS3) negatively regulates leptin-mediated activation of JAK2/STAT3 signaling by binding tophosphorylated JAK2 proteins [52,53]. Recently, SOCS3 has beenreported to down regulate the expression of anti-apoptotic proteinsurvivin through binding with long isoform of leptin receptor (Ob-Rb) and thus inhibiting leptin signaling through JAK/STAT pathway[54].

In a recent study, leptin has been shown to be involved in theregulation of endothelial cell proliferation and in the promotion ofangiogenesis [55]. Leptin increases endothelial COX-2 expression

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513 505

through p38 MAPK and PI3K/Akt activated mechanisms [56]. Inmouse mammary cancer cells, leptin may promote angiogenesisthrough vascular endothelial growth factor (VEGF) signaling, asleptin treatment results in increased expression of genes for VEGFand VEGF receptor-2 (VEGF-R2) in these cells [57].

Leptin promotes the synthesis of estrogens or converselyreduces follicular estradiol secretion and thus may influencebreast cancer risk [58,59]. Leptin exerts its effects by increasingcell viability and proliferation through crosstalk with estrogenreceptor-alpha (ERa). The expression of leptin receptor (Ob-R)and its signaling correlates with the presence of ERa in humanbreast cancer cell lines [60]. Leptin receptor expression was alsofound to be positively correlated with ERa expression in primarybreast carcinoma, which further illustrates the positive associa-tion between estrogen and leptin systems in the development ofbreast cancer in human. In a study on breast cancer patients, theserum leptin level was found to be higher in tamoxifen-treatedpatients as compared to controls [61,62]. The possible explana-tion for this is that the binding of tamoxifen reduces theexpression of ER which results in concomitant decrease in theleptin receptor expression and ultimately an increased serumleptin level.

Leptin induces the functional activation of estrogen receptors inMCF-7 cells via the extracellular signal-regulated kinase 1 and 2(ERK1/ERK2) signal transduction pathway [63]. The antiestrogeniceffects of ICI 182,780 on MCF-7 cells have been shown to be ceasedby simultaneous treatment with leptin [64]. This study furtherproved that leptin results in ER activation which neglects theeffects of antiestrogenic compound by an unknown mechanism. Ina preclinical tumor model for breast cancer, tamoxifen andletrozole did not affect leptin level in the serum [65]. In anotherstudy, treatment with exemestane caused 27% decrease in plasmaleptin levels following about 3 months of treatment in postmeno-pausal breast cancer patients [66]. This differential effect might bedue to menopausal status or time duration after which plasmaleptin level was measured. Leptin can also transactivate HER-2 inbreast cancer cells through both the HER-1 and JAK-2 pathways[67]. In a large number of breast tumors, leptin and its receptors arecoexpressed with HER-2, which supports the possibility ofintratumoral ob-R/HER-2 interactions. The circulating levels ofleptin are directly correlated with human telomerase reverse

transcriptase (hTERT) expression which is highly expressed inalmost all cancer types including breast cancer [68,69]. Thus, leptinis known to be a proliferative, self-renewal and survival factor inobesity-associated breast cancer.

Polymorphism of leptin (LEP) and leptin receptor (Ob-R) geneswas found to be associated with risk of developing breast cancer inobese women. LEP-2548G/A and LEPR Q223R polymorphisms maybe related to obesity as well as enhanced gene expression andincreased circulating levels of leptin [70–72]. The presence of LEP-

2548A/A and LEP-2548G/A in breast cancer cells was found to beassociated with high and intermediate leptin mRNA expression,respectively, while cells containing LEP-2548G/G expressed lowleptin mRNA levels. The presence of LEP-2548G/A facilitatesefficient recruitment of transcription factor specificity protein 1(Sp1) to leptin promoter DNA under insulin treatment, while Sp1loading on DNA containing LEP-2548G/G was not insulin-depen-dent. In contrast, the binding of nucleolin, a transcriptionalrepressor to LEP-2548G/A was downregulated in response toinsulin, while it was not regulated on LEP-2548G/G [73]. Thus, thepresence of LEP-2548G/A might enhance leptin expression in breastcancer cells via Sp1- and nucleolin-dependent mechanisms andthis enhanced leptin expression is associated with breast cancerrisk. In a case–control study, a modest increase in risk ofdeveloping breast cancer was found to be associated with LEP-

2548A/A genotype compared to the LEP-2548G/G genotype and the

association was stronger among the postmenopausal women whowere obese [74].

2.3.2. Adiponectin

Another adipokine involved in obesity-associated breast canceris adiponectin, which is mainly secreted by adipocytes and someamount is also secreted by other types of cells [75,76]. It has amolecular weight of 28–30 kDa. Several isoforms of adiponectinhave been identified. Amongst them, full length adiponectinknown as Acrp30 and globular adiponectin known as gAcrp30 areimportant because of their strong and identified affinity withadiponectin receptors [77]. There are mainly two adiponectinreceptors (AdipoRs), AdipoR1 and AdipoR2. Of these, AdipoR1 hashigh affinity for gAcrp30 and AdipoR2 is the intermediate affinityreceptor for gAcrp30 and Acrp30 [75,78]. The altered expression ofadiponectin receptors have been reported in most of the breastcancer cell lines such as MDA-MB-231, MCF-7, T47D and SK-BR-3.The variation is found in the expression levels of AdipoR1 andAdipoR2 in breast cancer cell lines. MDA-MB-231, T47D, and MCF-7 cells showed higher expression of AdipoR1 and lower expressionof AdipoR2, whereas MDA-MB-361 cells showed higher expressionof AdipoR2 [79–81].

Several retrospective and prospective case–control studies haveproved the association of low serum adiponectin levels withincreased risk of breast cancer. There is a controversy on whetherlow adiponectin level increases the risk of breast cancer amongboth premenopausal and postmenopausal women or it isassociated with increased risk only in postmenopausal women.Some studies have reported that there is a well defined inverseassociation between adiponectin and breast cancer risk in bothpre- and post-menopausal women. In contrast, some other studieshave reported that lower adiponectin levels are associated withbreast cancer risk only in postmenopausal women [82–87]. Thesedifferences might be due to female sex hormones especially theestrogens since serum adiponectin concentration is inverselycorrelated with serum estradiol concentration in postmenopausalwomen but not in premenopausal women [88].

Addition of full length adiponectin, i.e. Acrp30 to ER-positivecell lines (MCF-7, T47D, and MDA-MB-361) results in increasedapoptosis by increased poly (ADP-ribose) polymerase (PARP)cleavage. Increase in cleaved caspase-8 on adiponectin treatmentwas also found in MDA-MB-231 and MCF-7 cells leading toapoptosis. The treatment of MDA-ERa7 cell line (produced bytransfection of ERa gene into MDA-MB-231 cell line) withtruncated form of adiponectin, i.e. gAcrp30 reduces its growthprobably by decreasing phosphorylation of JNK2 [79]. This studyshows that ER expression is important for signaling throughadiponectin receptors and consequently cell growth inhibition byadiponectin treatment. Estrogen has been found to suppressadiponectin expression in 3T3-L1 adipocyte cell line [89]. Thissuggests that estrogen might be an important factor in obesity-induced breast carcinogenesis through decreased adiponectinexpression in adipocytes of adipose tissue.

The anti-proliferative and pro-apoptotic effects of adiponectinmight be mediated by its binding to AdipoRs, and concomitantactivation of AMP-activated protein kinase (AMPK), and theinactivation of p42/p44 MAPK [90]. Adiponectin mediated activa-tion of AMPK is involved in anti-breast cancer activities throughregulation of PI3K/Akt pathway [91]. In MDA-MB-231 cells,adiponectin-activated AMPK reduces cell invasion by inducingAKT dephosphorylation through protein phosphatase-2 activity[92]. Adiponectin may also mediate its effects by regulating theexpression of different tumor suppressor genes, oncogenes, pro-and anti-apoptotic genes, and cell cycle regulatory genes includingp53, Bax, Bcl-2, c-myc, cyclin D1, MAPK3 and ataxia telangiectasia

mutated (ATM) [80,90]. Adiponectin significantly inhibits the cell

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513506

proliferation induced by leptin, oxidized low-density lipoprotein(LDL) and several other growth factors like platelet-derived growthfactor subunit B homodimer (PDGF-BB), basic fibroblast growthfactor (bFGF), and heparin-binding epidermal growth factor-likegrowth factor (HB-EGF) [93–95]. Adiponectin inhibits the serum-induced phosphorylation of AKT and glycogen synthase kinase-3b(GSK-3b) and suppresses the intracellular accumulation of b-catenin in MDA-MB-231 and T47D breast cancer cell lines. Thisshows that GSK-3b/b-catenin signaling pathway is involved inadiponectin-mediated growth inhibition in breast cancer cell lines[95]. Thus, adiponectin acts as anti-proliferative, pro-apoptotic andinhibitor of angiogenesis in breast cancer. Fig. 1 summarizes themain signaling pathways mediated by estrogen, leptin andadiponectin which are involved in the process of breastcarcinogenesis.

2.4. Tumor microenvironment

The tumor microenvironment comprises of cells, solublefactors, signaling molecules, and extracellular matrix that canpromote tumorigenesis, and resist the tumor from host immunityand therapeutic response. Obesity reduces the oxygen level in thetumor microenvironment leading to hypoxic condition [97].Hypoxia in the peri-tumoral fat is reported to promote tumorsite hypoxia. The up regulation of hypoxia-inducible factor-a (HIF-1a) takes place in the hypoxic state which leads to alteredexpression of several genes involved in angiogenesis, cellproliferation and apoptosis which ultimately results in cellular

Fig. 1. Estrogen, leptin and adiponectin signaling in breast carcinogenesis. The signaling

leptin and adiponectin) is shown here. Estrogen binding to estrogen receptor-a (ERa) in

nucleus and binds to estrogen responsive elements (EREs) at the promoter region of some

adipose tissue is directly correlated with the breast cancer progression. Leptin binds to it

JAK2/STAT3 pathway, PI3K/AKT pathway, and MAPK pathway (here we shown only JAK2

binds to cytoplasmic domains of leptin receptor and causes their phosphorylation which

and the dimerized STAT3 binds at the promoter region of some tumor promoting genes (e

genes (e.g. survivin) and leads to their expression. Leptin has its actions not only through

increases the expression of aromatase and thus causes increased estrogen synthesis. In th

dependent pathway [96]. The low level of adiponectin results in abrogated adiponectin s

end result of all of these signaling pathways is increased cell proliferation and surviva

adaptation to low oxygen concentration [98]. In the adipose tissue,hypoxia induces the secretion of pro-angiogenic and inflammatorycytokines [99,100]. Hypoxia down regulates the expression ofCCAAT/enhancer binding protein-a (C/EBPa) in T-47D breastcancer 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-associatedbreast cancer

3.1. Hormones- and growth factors-targeted

Despite the significant heterogeneity, several advances havebeen made over the past decade for the care of patients with breastcancer. Available treatments for breast cancer include chemother-apy, radiotherapy, hormonal and targeted therapy. Anthracyclines(e.g. doxorubicin) and taxanes (e.g. docetaxel) are two mostcommonly used chemotherapeutic agents for the treatment ofbreast cancer. These days, targeted and hormonal therapies areshowing promising results in the prognosis of breast cancer.Agents used in targeted therapy include inhibitors of receptortyrosine kinases (epidermal growth factor family inhibitors, e.g.gefitinib and erlotinib) and nonreceptor tyrosine kinases, inhibi-tors of intracellular signaling pathways such as PI3K/Akt and Ras-Raf MAPK, angiogenesis inhibitors, agents that interfere with DNArepair (e.g. PARP inhibitors), and hormonal antagonists. The use of

through three major players involved in obesity-associated breast cancer (estrogen,

the cytoplasm leads to ERa dimerization. This dimerized ERa passes through the

tumor promoting genes and leads to their expression. The high level of leptin in the

s cell surface receptor and leads to activation of several oncogenic pathways such as

/STAT3 pathway, the major pathway activated by leptin). The phosphorylated JAK2

ultimately leads to phosphorylation of STAT3. The dimerization of STAT3 takes place

.g. c-myc, EGFR, and src), cell cycle promoting genes (e.g. Cyclin D1) or anti-apoptotic

leptin receptor but it also has crosstalk signaling with estrogen receptor-a. Leptin

e absence of estrogen, leptin also stimulates signaling through ERa through MAPK-

ignaling through activation of MAPK pathway and inhibition of AMPK pathway. The

l and/or decreased apoptosis and ultimately the induction of breast cancer.

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513 507

targeted therapies such as estrogen antagonist (e.g. tamoxifen andfulvestrant) in estrogen receptor (ER) positive cases and ofmonoclonal antibody trastazumab (Herceptin) for the inhibitionof signaling through HER-2 receptor have contributed significantlyto these advances [103]. Mammalian target of rapamycin (mTOR)inhibitors (e.g. everolimus) which target mTOR pathway is a newlyadded targeted therapy in breast cancer treatment [104].

Combination therapy has proven to be more effective approachthan the mono-agent therapy for breast cancer treatment.Targeting HER-2 with trastazumab and VEGF with bevacizumabin combination with chemotherapy is more effective than singleagent in the treatment of breast cancer [105]. The combination ofaromatase inhibitor (letrozole) and HER-2 inhibitor (trastazumab)is an effective therapy in hormonal-refractory breast cancer due tothe fact that the signaling through HER-2 increases in aromataseinhibitor resistant breast tumors [106,107]. Lapatinib, a dual-EGFR/HER-2 selective reversible inhibitor in combination withtrastazumab significantly improved the progression-free survival(PFS) in HER-2 over expressing breast cancer cells [105]. Thus, thiscombination of lapatinib and trastazumab can be effective in thetreatment of trastazumab-refractory metastatic breast cancer.

Reducing estrogen synthesis by targeting aromatase orinhibiting signaling through estrogen receptor could be atherapeutic option in obesity-associated breast cancer. Thearomatase inhibitors inhibit the estrogen synthesis and antiestro-gens inhibit and/or degrade estrogen receptor and consequentlyabrogate oncogenic signaling. Therefore, these two classes ofcompounds may be effective for treating obesity-related breastcancer. Tamoxifen shown to reduce serum IGF-I levels in obesewomen. Aromatase inhibitors such as letrozole reduce plasmaestrogen levels in obese postmenopausal women [108]. Thus, theseantiestrogens could be used to treat obesity-related breast canceras the levels of both IGF-I and estrogen were found to be increasedin obesity-associated breast cancer. Roscovitine is a selectivecyclin-dependent kinase (CDK) inhibitor which has found toreduce estrogen-induced phosphorylation of ERa at Ser118 inMCF-7 cells and thus inhibited signaling through ERa [109]. Theinhibition of signaling through JAK-2/STAT3 pathway by inhibitingSTAT3 or its upstream kinases may also be beneficial. Agents thatcould inhibit signaling through the insulin receptor might bepotential therapeutics in reducing insulin-mediated tumorgrowth.

FDA approved drugs such as phentermine, diethylpropion,phendimetrazine, orlistat and lorcaserin which are used in thetreatment of hyperlipidemia/hypercholesterolemia and obesitycan also be effective candidates for the treatment of obesity-related breast malignancies. Pitavastatin, a drug used for thetreatment of hyperlipidemia significantly reduced the develop-ment of diethylnitrosamine (DEN)-induced liver carcinogenesis in

Table 1Therapeutic agents in targeting hormones and growth factors for breast cancer treatm

Drug class Drug name Mode of action

Aromatase inhibitors Letrozole, anastrozole,

exemestane

Act through the inhib

aromatase, an enzym

the synthesis of estro

precursor hormones

Antiestrogens and estrogen

antagonists

Tamoxifen, fulvestrant Tamoxifen mainly ac

inhibition of ER. Fulve

through ER degradati

CDK-inhibitors Roscovitine Reduces phosphoryla

thereby inhibits dow

Anti-obesity and

anti-hyperlipidemia drugs

Orlistat, Pitavastatin Orlistat acts through

cycle progression, pro

apoptosis, and repres

db/db-obese mice. Orlistat has been found to inhibit growth ofbreast 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-associatedbreast cancer targeting hormones and growth factors are listed inTable 1.

Dietary and physical interventions such as reduction in high-fatdiet and increased physical activity can reduce the risk of breastcancer in postmenopausal women. A balanced energy budget ofbody controlled by limitation of calorie intake and/or by elevationof energy expenditure could be key ways to reduce obesity [115].The activation of AMPK by bioactive food components may be animportant strategy for the prevention of several cancers causeddue to increased BMI. AMPK plays an important role in cellularenergy homeostasis through the stimulation of fatty acid oxida-tion, inhibition of lipogenesis and modulation of insulin secretionby pancreatic beta-cells [116]. Thus, the phytochemicals thatactivate AMPK may also be useful in reducing the risk of obesity-mediated breast cancer in postmenopausal women.

3.2. Adipokines- and cytokines-targeted

Inflammatory cytokines and adipokines are potent targets forthe treatment of obesity-associated breast malignancy. Animportant strategy for the treatment of this class of cancer isthe development of pharmacological compounds that targetobesity-related pathways. There are various compounds that arebeing tested in clinical trials for obesity [117]. These compoundscan also be useful to treat obesity-associated breast tumorigenesispossibly in combination with anti-breast cancer agents. Fig. 2illustrates the various therapeutic agents and their targets inobesity and obesity-associated carcinogenesis.

The antagonists of leptin that can inhibit signaling through theleptin receptor and, adiponectin agonists that can mimic the actionof adiponectin could also be used to inhibit the growth of epithelialbreast cells. Pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the growth of breast cancer cells particularly ER-positive cells in xenograft mice model by reducing the expressionof 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 whichshows growth inhibitory effects on breast cancer cell lines as wellas on orthotopic xenograft breast cancer model [119].

Metformin, an anti-diabetic drug was found to reduce IL-6mRNA expression level and to enhance mRNA expression level ofIL-1R, the receptor for a naturally occurring anti-inflammatorycytokine. Action of metformin may be attributable to bemediated through the activation of AMPK pathway as silencingof AMPK-a1 results in lipopolysaccharide (LPS)-induced IL-6 and

ent.

Status References

ition of

e which catalyze

gen from its

Clinical phase III (with or without

chemotherapy) for invasive breast

cancer in postmenopausal women

[112]

ts through

strant mainly acts

on.

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)

[113,114]

tion of ERa,

nstream signaling

Preclinical [108]

blockade of cell

motion of

sion of HER2/neu

Preclinical [111,112]

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.

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513508

IL-8 expression [32]. Preclinical studies have demonstrated thatmetformin can inhibit the growth of breast cancer cells.Metformin mainly acts through the inhibition of signaling bymTOR pathway and leads to reduced expression of HER-2 proteinon breast cancer cells [31]. Thus, metformin may also showpromising results in the treatment of obesity-related breastcancer.

Table 2Synthetic molecules in targeting adipokines and inflammatory cytokines involved in o

Name of the compound Category Mode of action

Pegylated leptin peptide

receptor antagonist 2 (PEG-LPrA2)

Synthetic peptide Reduces the expres

angiogenic and pro-

ADP-355 Synthetic peptide Mimics the action

modulating key sig

an adiponectin-like

Aspirin Synthetic Anti-inflammatory

upregulation of pro

and downregulatio

proteins,

Celecoxib Synthetic Anti-inflammatory

Exemestane in combination

with celecoxib

Synthetic Aromatase inhibito

inhibitor

Infliximab Monoclonal antibody Anti-inflammatory

Metformin Synthetic Acts through either

of pro-inflammator

activation of AMPK

of mTOR pathway,

levels

Anti-inflammatory drugs which act through the inhibition ofkey inflammatory molecules such as IL-6, TNF-a and COX-2 canalso be used for treating obesity-associated breast cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin couldprevent the occurrence of cancers of epithelial origin includingbreast cancer as evidenced by in vitro, in vivo and epidemiologicalstudies. Aspirin has been found to promote apoptotic pathways in

besity-associated breast cancer.

Target/pathway Status Refs.

sion of pro-

proliferative factors

Leptin Preclinical [118]

of adiponectin by

naling pathways in

manner

Adiponectin Preclinical [119]

acts through

-apoptotic proteins

n of anti-apoptotic

COX-1 and COX-2 Preclinical [31]

COX2 Phase II completed [120]

r with COX-2 Aromatase And COX-2 Phase II completed [122]

TNF-a Phase II completed [123]

reduced expression

y cytokines and/or

pathway, inhibition

lowering IGF-1

AMPK, IGF-1, mTOR Preclinical [31,32]

Table 3Phytochemicals 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 Polyphenol Anti-inflammatory, fatty acid oxidation NFkB, and COX-2, PPARg Preclinical [129]

(-)-Catechin Flavanol Increases expression of adiponectin Adiponectin Preclinical [146,147]

EGCG Flavanol Promotes fat oxidation and inhibit adipocyte

differentiation, decreases fat absorption

AMPK, pancreatic lipases Preclinical [143,144]

Genistein Isoflavonoid Inhibitor of adipocyte differentiation AMPK, Fatty acid synthase Preclinical [139–141]

Isoquercitrin Flavones Prevents preadipocyte differentiation into adipocyte Wnt/b-catenin Preclinical [148,149]

Myricetin Flavones Inhibits lipid droplet accumulation in adipocytes Peroxisome proliferator-activated

receptor-a (PPARa)

Preclinical [150]

Quercetin Flavone Anti-inflammatory, inhibits adipocyte cell growth COX-2, NFkB and TNF-a Phase I [136]

Resveratrol Polyphenol Anti-inflammatory, inhibits adipocyte differentiation IL-6, TNF-a and NFkB, AMPK, PPARg Preclinical [131]

Ursolic acid Triterpenoid Anti-inflammatory NFkB, and COX-2 Preclinical [127,137,138]

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513 509

cancer cell lines by up regulation of pro-apoptotic and downregulation of anti-apoptotic proteins [31]. There are several otherdrugs in clinical trials for the treatment of obesity and/or obesityassociated breast cancer targeting cytokines and inflammatorymediators, which are further listed in Table 2. Celecoxib, a COX-2inhibitor successfully completed phase II clinical trial for thetreatment of postmenopausal breast cancer [120]. Exemestane, anaromatase inhibitor in combination with avandamet (combinationof rosiglitazone and metformin) was found to be effective in phase Iclinical trial to treat breast cancer in obese postmenopausalwomen [121]. The combination of Exemestane and Celecoxib wastested in phase II clinical trial for the treatment of breast cancer inobese postmenopausal women and found to be effective [122].Infliximab, a monoclonal antibody targeting TNF-a completedphase II clinical trial for the treatment of cancer related fatigue inpatients who had undergone breast cancer treatment [123]. In apilot study, docosahexaenoic acid (DHA), an omega-3 fatty acid,reduced inflammation and aromatase expression in obesepostmenopausal women [124]. Further clinical studies on theefficacy of DHA against breast cancer are currently ongoing. Greentea extract is being tested in phase II clinical trial in healthypostmenopausal women [125]. (-)-Catechin, one of the compo-nents of green tea is in phase I clinical trial for treating women withhormone receptor-negative stages I–III breast cancer [126]. Theefficacy of these drugs could also be tested in obesity-associatedbreast cancer possibly in combination with anti-breast cancerdrugs.

Phytochemicals found in fruits, vegetables have also showntheir efficacy against obesity and obesity-associated cancers.Curcumin, phytochemical found in turmeric, is an anti-inflamma-tory agent and shown to modulates NFkB, Stat3, COX-2, Akt, andmTOR pathways [127,128]. By targeting these obesity-relatedpathways, curcumin reduces the symptoms of obesity such ashyperglycemia and hyperlipidemia and thus inhibits obesity-associated tumor growth [129,130]. Resveratrol, a dietary poly-phenol generally found in grapes, shown to inhibit inflammatorycytokines and chemokines [131–133]. Quercetin generally foundin citrus fruits, onions, tea and red wine possesses anti-inflammatory and anti-oxidant activities. It alters Akt/mTORpathway, COX-2 expression, NFkB signaling, TNF-a expression,and VEGF expression [134,135]. A phase I clinical study showedthat quercetin inhibits tumor growth and inflammation [136].Ursolic acid is a triterpenoid found in rose-mary, shown to be anti-inflammatory and insulin sensitizing in nature [127,137]. Ursolicacid also inhibits VEGF and other inflammatory growth factors inmice, thus it could also be an anti-angiogenic agent [138]. Hence,these anti-inflammatory and anti-angiogenic phytochemicalscould be designed to test their efficacy either alone or incombination with available therapeutic agents against obesity-associated breast cancer.

Dietary flavonoids such as genistein and (�)-catechin exertsanti-obesity effects either by promoting fatty acid oxidation or byinhibiting adipocyte differentiation [139–147]. Genistein is foundin soy (Glycine max) and soy food products. Genistein inhibitsadipocyte differentiation probably by promoting AMPK-activation[139,140]. Genistein was also found to inhibit fatty acid synthaseexpression and JAK2 phosphorylation which indirectly leads tosuppression of adipocyte differentiation [141]. EGCG and (�)-catechin are components of green tea and known as green teapolyphenols. EGCG was reported to have pancreatic lipaseinhibitory activity and was also found to inhibit adipocytedifferentiation by AMPK-activation [142–145]. Similar to EGCG,(-)-catechin also activates AMPK and inhibits adipocyte differenti-ation. In addition to this, (-)-catechin also increases the expressionof adiponectin [146,147]. Isoquercitrin and myricetin are flavonesthat also exert anti-obesity effects. Isoquercitrin activates wnt/b-catenin signaling, thus inhibits preadipocyte differentiation intoadipocytes [148,149]. Myricetin activates PPARa and inhibits lipiddeposition in adipocytes [150]. Phytochemicals with differentphases of their preclinical and clinical development against obesityand 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 followedto reduce the number of obesity-associated breast cancer cases.Reduction of high calories in diet by reducing the consumption offat-rich diet and increased physical activity are the two mostimportant prevention strategies for obesity and ultimately forobesity-associated breast cancer. Development of more effectivedrugs that can selectively inhibit the estrogen synthesis withminimal side effects might be useful candidates against obesity-associated breast cancer. More research needs to be focused on thedevelopment of effective leptin antagonists and adiponectinagonists. Therapeutic agents that can reduce energy metabolismand induce adipocyte degeneration might also prove to be effectivecandidate drugs. Combination of chemotherapy and hormonaltherapy or different hormonal therapies is to be tested in theclinical trials. Future research on the efficacy of anti-obesity drugssuch as pitavastatin and orlistat in the treatment of obesity-relatedmammary carcinogenesis is also needed. The efficacy of anti-diabetic drug metformin against breast cancer needs to be tested inclinical trials as it has shown its efficacy in preclinical trials. Moreresearch is also needed on the efficacy of anti-inflammatory drugsagainst obesity-associated breast cancer.

5. Conclusion

Obesity is a strong risk factor for the increased breast cancerincidence and mortality in postmenopausal women. The detailed

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513510

molecular mechanisms involved in obesity-associated breastcancer need to be studied. However, the known signaling pathwaysinvolved in obesity-associated breast cancer are mediated throughestrogen, insulin, leptin, adiponectin and inflammatory cytokines.In fat cells, increased aromatase activity leads to an increase inestrogen synthesis which further decreases the level of SHBG, bothcausally linked with obesity-associated breast cancer. The levels ofInsulin and insulin like growth factors are increased in obesitywhich increases the growth rate of cancer cells via activation of keytumorigenic pathways such as PI3K/Akt/mTOR and Ras/Raf/MAPK.The increased leptin and/or decreased adiponectin levels are thestrong risk factors for the development of postmenopausal breastcancer. Obesity-inflammation axis plays an important role in thedevelopment of breast cancer. In obese condition, increasedproduction of inflammatory cytokines has been found which arepotentially linked to breast cancer development via severalmechanisms including cellular proliferation and genetic damage.The therapeutic regimens for obesity-associated breast cancerinclude aromatase inhibitors, estrogen antagonists, leptin antago-nists, adiponectin agonists, and anti-inflammatory drugs. Howevertheir 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 theCouncil of Scientific and Industrial Research (CSIR), Government ofIndia, India. Part of this work was also supported by grants toS.M.M. from the Science & Engineering Research Board (SERB), NewDelhi, India. We thank Ms. Isha Soni for her assistance in proof-reading the manuscript. CSIR-CDRI communication Number-8554.No conflict of interest.

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Syed Musthapa Meeran Ph.D is currently a senior sci-entist at the Division of Endocrinology of CSIR-CentralDrug Research Institute. In his doctoral work, he studiedthe role of asbestos and other biomass pollutants-me-diated genetic and cytogentic changes in the pulmonarysystem. To further in his postdoctoral study, he evalu-ated the role of inflammatory cytokines for the skincancer risk at the Department of Dermatology, Univer-sity of Alabama at Birmingham. Later he became afaculty at the Department of Biology, University ofAlabama at Birmingham, where he studied the epige-netic and chemoprevention of breast cancer. He is cur-rently working on the novel genetic and epigenetic

targets for breast and lung cancer prevention as well as therapy with bioactivedietary supplements. His research interest are also focused on the role of variouscytokine and chemokine mediated intra cellular signaling in the cancer progression,especially breast cancer.

Sajid Khan obtained his Masters degree in Biotechnol-ogy from Aligarh Muslim University, Aligarh, India in2011. Currently, he is working as a doctoral researchfellow under the guidance of Dr. Syed Musthapa Meeranin the Endocrinology Division of CSIR-Central Drug Re-search Institute, Lucknow, India. His research work isprimarily focused on the role of leptin and adiponectinin obesity-associated breast cancer. He also obtainedSenior Research Fellowship (CSIR-SRF) from the Councilof Scientific and Industrial Research, New Delhi, Indiafor his doctoral study.

S. Khan et al. / Cytokine & Growth Factor Reviews 24 (2013) 503–513 513

Samriddhi Shukla has received her Masters degree inBiotechnology from Dr. R.M.L. Avadh University, Faiza-bad, India with university ranking and gold medal. She iscurrently pursuing her doctoral research under thementorship of Dr. Syed Musthapa Meeran, CSIR-CentralDrug Research Institute, Lucknow, India. Her researchwork mainly focuses on the genetics and epigenetics oflung cancer. She also obtained Senior Research Fellow-ship (CSIR-SRF) from the Council of Scientific and In-dustrial Research, New Delhi, India for her doctoralresearch work.

Sonam Sinha earned her Masters in Biotechnology fromAMITY University, Lucknow, India in 2011. She is cur-rently engaged as a Project Assistant under the super-vision of Dr. Syed Musthapa Meeran at CSIR-CentralDrug Research Institute, Lucknow, India. Her researchinterest is mainly focused on studying novel genetic andepigenetic targets for breast cancer prevention andtherapy with bioactive dietary supplements.