Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1.

Abstract

Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer. As a key mediator of adipogenesis and regulator of adipokine production, peroxisome proliferator-activated receptor-γ (PPAR-γ) is involved in PAI-1 expression from adipose tissue. We summarize the current knowledge linking PPAR-γ and PAI-1 expression to high-fat diet and obesity in the risk of breast cancer.

Full text

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Hindawi Publishing Corporation
PPAR Research
Volume 2009, Article ID 345320, 13 pages
doi:10.1155/2009/345320
Review Article
ObesityandBreast Cancer:TheRolesof Peroxisome
Proliferator-Activated Receptor-γ and Plasminogen
Activator Inhibitor-1
JenniferC.Carter1andFrank C.Church1,2,3
1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill,
NC 27599-7035, USA
2Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
3Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill,
NC 27599, USA
Correspondence should be addressed to Frank C. Church, fchurch@email.unc.edu
Received 3 February 2009; Revised 18 May 2009; Accepted 10 June 2009
Recommended by Sarah J. Roberts-Thomson
Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with
development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1)
is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer. As a key mediator of
adipogenesis and regulator of adipokine production, peroxisome proliferator-activated receptor-γ (PPAR-γ) is involved in PAI-1
expression from adipose tissue. We summarize the current knowledge linking PPAR-γ and PAI-1 expression to high-fat diet and
obesity in the risk of breast cancer.
Copyright © 2009 J. C. Carter and F. C. Church. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
1.Introduction
1.1. Breast Cancer Epidemiology. Breast cancer is the most
commonly diagnosed cancer in the female population and
is second in cancer related deaths in the United States
[1]. While the mortality has decreased slightly in recent
years, the number of cases diagnosed annually has remained
relatively steady. According to the American Cancer Society,
over 178000 new cases are diagnosed each year, with an
estimated 40 400 deaths from breast cancer in 2008 [1]. Five-
year survival rates of breast cancer patients is almost 90%,
although higher in patients over 40, as women diagnosed at
ayoungagetypicallyhaveamoreaggressivecancerthatisless
responsivetotreatment[1].Thoughbothincidenceratesand
mortality rates have decreased in recent years, the healthcare
costs and the emotional costs of breast cancer remain high.
Anumberofriskfactorsareassociatedwithdevelopment
of breast cancer. The greatest risk factors are age and
gender, with females developing breast cancer 100 times
more frequently than males [2]. As a woman ages, her
risk of developing breast cancer increases, from 1 in 233
between the ages of 30–39 to 1 in 27 between the ages of
60–69. While age and gender are the greatest risk factors,
there are also hormonal risk factors associated with breast
cancer development, including age at first menarche, age
at menopause, and lifetime exposure to estrogen [3, 4].
Furthermore, a family history of breast cancer and a history
of previous benign breast disease are risk factors associated
with breast cancer [5].
1.2. Breast Anatomy. The breast is a very heterogeneous tis-
sue, composed of a number of different cell types. Epithelial
cells make up the parenchyma of the tissue, forming the
ducts and glands involved in milk production, storage, and
secretion [5]. Surrounding these epithelial cells is a network
of fibroblasts, which generate the proteins of the breast
connectivetissue[5].Anotherkeycomponentofbreasttissue

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is adipose, composed of mesenchymal precursor cells and
the mature adipocytes [5]. In addition to energy stores,
adipocytes synthesize and secrete a number of cytokines,
which are involved in a number of pathogenic processes,
including inflammation [6].
Our interest in the adipose tissue of the breast stems
from the understanding that the tumor microenvironment
provides a number of signals and resources to the tumor
cells, promoting proliferation, survival, and motility. In that
regard, adipocytes, or their precursor cells, may provide
key factors in breast tissue needed for tumor development,
progression,orevenenabletumorcellinvasion.Additionally,
several recent studies suggest a woman with dense breast
tissue is more at risk for developing breast cancer [7–
9]. Collectively, these results imply that excess amounts of
adipose in either the breast or other distant fat depots could
provide a climate amenable to development of carcinoma of
the breast.
The overall goal of this paper is to present evidence
supporting the link between how a high-fat diet and obesity
increasestheriskofbreastcancer.Wefocusontheexpression
of the nuclear receptor peroxisome proliferator-activated
receptor-γ (PPAR-γ) and the serine protease inhibitor (ser-
pin) plasminogen activator inhibitor-1 (PAI-1).
2.Tumor Progressionand Metastasis
In order for a cancer cell to progress to a disease state, the cell
must be able to proliferate and generate a clonal population,
resulting in a tumor [10]. To do the most harm, cancer
cells must possess the ability to survive and migrate from
their site of origin. Motility allows these cells to move from
primary sites, such as the breast, to distant metastatic sites
[11]. In terms of breast cancer, the most common sites of
metastases are bone, brain, and lung [5]. In order to move
to distant sites, these cells must degrade the surrounding
extracellular matrix (ECM) and invade nearby blood and
lymph vessels [12]. The plasminogen activator (PA) system
allows tumor cells to activate plasminogen, resulting in the
active proteolytic enzyme plasmin and ECM degradation
[13]. In breast cancer, this system is often dysregulated,
resulting in migration and invasion of tumor cells into the
surrounding vasculature and lymphatics [14].
Recently the tumor microenvironment has come into the
forefront as a possible source of either help or hindrance
to the tumor. As mentioned previously, the breast is largely
madeupoffibroblasts,connectivetissue,andadipose.PPAR-
γ is a key regulator of adipogenesis [15–17], and there is
growing evidence of its importance in many pathophysi-
ological processes [17–20]. PPAR-γ has been shown to be
dysregulated in the obese population [21], and since obesity
is a known risk factor for breast cancer development, PPAR-
γ activity may have a role in breast cancer inhibition. Several
studies have suggested that activation of PPAR-γ inhibits cell
proliferation and induces apoptosis in vitro [22–26]. PPAR-
γ has been found to regulate PAI-1 expression in endothelial
cells, smooth muscle cells, and pancreatic cell lines [27–
29].
3.The Plasminogen ActivatorSystemin
Breast Cancer
The role of the PA system is to regulate fibrinolysis and
to promote pericellular proteolysis [30]. Plasminogen is
cleaved by a plasminogen activator to its active serine
protease, plasmin. Tissue-type plasminogen activator (tPA)
mediates plasminogen activation in the vasculature. Plasmin
then hydrolyzes fibrin, restoring hemostasis. Outside of this
fibrinolytic pathway, the PA system also plays a role in tumor
cell invasion (Figure 1). In the pericellular environment,
the serine protease urokinase plasminogen activator (uPA)
is primarily responsible for the cleavage of plasminogen.
Plasmin is then able to degrade the extracellular matrix
(ECM) directly or indirectly by activation of promatrix
metalloproteinases, which then degrade the ECM [31, 32].
PlasminalsoactivatesmoreuPA,formingapositivefeedback
loop that further supports invasion-linked processes. In
addition to these roles, the cell surface uPA receptor (uPAR)
plays a role in integrin mediated cell motility. Bound to
uPA, uPAR is able to bind various integrins, resulting
in the rearrangement of the cytoskeleton, promoting cell
motility. Elevated uPA is a poor prognostic indicator in a
number of cancers, including carcinoma of the breast [33–
36]. The serine protease inhibitor (serpin) PAI-1 binds to the
active site of uPA, blocking the activation of plasminogen
to plasmin. PAI-1 also affects cell adhesion and migration
though binding of the uPA/uPAR complex. The PAI-1/uPA
complex is recognized by lipoprotein-related protein (LRP),
a scavenger receptor, and is rapidly internalized; uPA and
PAI-1 are then degraded and uPAR is recycled to the cell
surface [37]. Since elevated PAI-1 levels are an indicator
of poor prognosis in breast cancer, this data would suggest
increased amounts of PAI-1 result in a deattachment of the
cellfromtheECM,allowingforenhancedcellmotility.These
tumor cells could then invade into the surrounding blood
vessels and lymphatics, becoming metastases of the primary
cancer.
3.1. Urokinase Plasminogen Activator. Urokinase plasmino-
gen activator (uPA) is a 53kDa serine protease. Initially
a zymogen, pro-uPA is cleaved to the active form [38].
Though the physiological activator is unknown, in vitro a
numberofproteasescanactivateuPA.Inadditiontoprotease
cleavage, binding the uPA cell surface receptor uPAR can
activate pro-uPA. uPA functions to cleave plasminogen to its
active protease plasmin. In 1978, Verloes et al. demonstrated
inhibition of uPA resulted in tumor growth inhibition,
implicating a pathological role for uPA [39]. Since this
discovery, uPA has been shown to be involved in tissue
remodeling, inflammation, fertilization, embryogenesis, and
tumor invasion [40, 41].
3.2. Urokinase Plasminogen Activator Receptor. The cell-
surface receptor for uPA (uPAR) is a 55–60kDa protein.
It has no transmembrane domain; it is anchored to the
cell surface by a glycosyl phosphatidylinositol anchor. uPAR
is required for the endocytosis of uPA/PAI-1 complexes

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PPAR Research3
Cell membrane
Urokinase receptor (uPAR)
Extracellular matrix (ECM)
Plasmin
Urokinase (uPA)
ECM
degradation
PAI-1
Plasminogen
Integrin
GPI
Tumor cell
Plasminogen
LRP
MMP’s
proMMP’s
Tumor cell invasion
PAI-1
ECM proteins
Integrin binding site (RGD)
VN somatomedin B domain:
PAI-1 and uPAR binding site
PAI-1
Vitronectin
uPAR
uPAR
uPA
uPA
Ternary complex (PAI-1/uPA/uPAR)
internalization and cell signaling
βα
Figure 1: Plasminogen Activator System at the Tumor Cell Surface. Besides its traditional role as a protease inhibitor, the multiple roles of
PAI-1 including cell de-adhesion, proliferation/apoptosis, and cell signaling suggest that PAI-1 expression in the tumor microenvironment
enhances tumor cell progression. (Left panel) The catalytic activity of urokinase (uPA) is enhanced when bound to the cell surface by
uPAR. uPA cleaves the zymogen plasminogen to its active form, the serine protease plasmin. Plasmin can subsequently activate matrix
metalloproteases (MMP’s) in the extracellular matrix (ECM) microenvironment. Thus, the uPA/uPAR complex and MMP activation
contribute to tumor cell invasion and metastasis by degradation of ECM components. (Middle panel) PAI-1 directly inhibits the active
site of uPA whether it is free or bound to uPAR, and reduces further activation of plasminogen to plasmin. The PAI-1 paradox exists because
this inhibition reaction should reduce tumor cell progression and invasion. (Right panel) When uPA is neutralized by PAI-1, the trimeric
PAI-1/uPA/uPAR complex is recognized by the lipoprotein related protein (LRP) and internalized. Furthermore, PAI-1 has vitronectin (VN)
binding sites and causes tumor cell detachment away from the ECM. This figure is based on a schematic from [13].
and plays a key role in uPA activation. Research has also
shown uPAR mediates cell proliferation through activation
ofERK/MAPkinasepathwaysfollowingbindingofuPA[42].
Examination of uPAR protein levels in several breast cancer
cell lines showed a correlation with invasiveness in vitro
[43]. In breast cancer patients, combined overexpression of
uPAR,PAI-1,anduPAwasshowntocorrelatewithdecreased
survival [44].
3.3. Plasminogen Activator Inhibitor Type-1. PAI-1 is a gly-
coprotein of approximately 50kDa [45] and a member of
the serine protease inhibitor (serpin) superfamily of proteins
[46]. PAI-1 binds the active site of tPA [47, 48] and uPA,
preventing cleavage of plasminogen. Binding of PAI-1 to
vitronectin (VN), which stabilizes the protein in blood
circulation [49]. While the physiological role of PAI-1 is
to inhibit plasminogen activation, it is a poor prognostic
indicator for a number of cancers, including breast cancer
[14, 50, 51]. There is no single mechanism to explain why
an elevation in PAI-1 protein results in decreased patient
survival, but there are a number of studies that suggest
alternative roles for PAI-1 outside of the traditional protease
inhibitor role. Specifically, several studies indicate that PAI-1
promotes tumor growth through an inhibition of apoptosis
[23, 26, 52]. PAI-1 has also been implicated in angiogenesis
[53, 54], increased cell adhesion [55], and increased migra-
tion [56]. In addition to the role of PAI-1 in breast
cancer migration and invasion, it has been implicated in
an inflammatory response [57], neutrophil recruitment, and
in proliferation of smooth muscle cells [58]. Furthermore,
increased PAI-1 levels have been associated with obesity [59–
62], with recent reports suggesting the elevation in PAI-1
levels is the result of PAI-1 production from adipocytes [63–
65].
4.ObesityandBreast CancerRisk
A number of factors are associated with an increased risk of
developing breast cancer (Table 1). While age and gender are
the two predominant risk factors, some risk factors remain
modifiable, such as diet and obesity [66–68]. Adult weight
gain is correlated with increased breast cancer risk and is
a poor prognostic factor [69]. The mechanism behind the
relationship of increased incidences of breast cancer in obese
individuals is poorly understood; however, the literature
concerning this association has increased in recent years
[70, 71].
Besides their traditional role as energy stores, adipocytes
are now considered to be an important “endocrine gland”,

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Table 1: Relationship between obesity, PPAR-γ, fatty acids, and increased risk of breast cancer
ComponentAssociation with obesity Association with breast cancer
Primary source
PAI-1
Breast epithelial cells,
endothelial cells, smooth
muscle cells, adipocytes
[61, 72] [14, 73]
uPAUnknown
Tumor cells, epithelial
cells
[14, 74]
uPARUnknown
Monocytes, neutrophils,
epithelial cells, tumor
cells
[32]
TNF-α
Macrophages,
adipocytes, lymphocytes
[61, 64][75]
Aromatase
Breast epithelium, [76]
endometrium,
adipocytes
[77][78, 79]
Leptin
Adipocytes
[6][71, 80, 81]
Adiponectin
Adipocytes [82, 83]
[6, 84][80, 85]
PPAR-γ
Adipocytes, tumor cells
[86, 87][88, 89]
ω-3 FA
Diet
[90, 91][92, 93]
ω-6 FA
Diet
[90, 91][94, 95]
expressing numerous proteins involved in several physio-
logical and pathological responses [64, 96]. Aromatase, the
enzyme needed to activate estrogen, is one of the factors
expressed by adipose tissue. Recently it was suggested that
stromal cells in the adipose tissue, not adipocytes, express
aromatase [77–79, 97]. Elevated aromatase in the breast
correlates to elevated levels of estrogen in the breast [97].
It is hypothesized this is a key reason for the increased
risk of developing breast cancer in obese postmenopausal
women.
Another factor expressed in the adipose tissue is the
hormone leptin. In obese individuals, leptin is overex-
pressed [98]. In vitro, leptin has been shown to increase
cell motility and decrease cell apoptosis in breast cancer
cell lines [68, 82]. The mature adipocyte also expresses
adiponectin. As opposed to the overexpression of leptin
in obese individuals, adiponectin is downregulated [6, 99].
Grossmanetal.showedthebalanceofadiponectinandleptin
mediated breast cancer cell growth in vitro [80]. Studies
have shown an antitumor effect of adiponectin in breast
cancer. Treating cells with adiponectin decreases cell motility
and induces apotosis [85]. Furthermore, adipocytes express
several chemokines involved in the inflammatory response.
A number of other adipokines are associated with cancer
progression and metastasis, including PAI-1 [64, 65, 100].
As stated previously, obese individuals have elevated serum
levels of PAI-1 [59, 101]. Interestingly, one study found
an inverse relationship between adiponectin and PAI-1
expression in overweight and obese women [57]. With
elevated plasma levels of PAI-1 from the adipose tissue, it is
possible obese women are more prone to developing breast
cancer and having a more aggressive disease. Prostate cancer
cell growth in vitro is enhanced by this cancer cell-adipocyte
communication;thus,itis interesting tospeculatethatbreast
cancer cell-adipocyte interactions would behave in a similar
manner.

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5.PeroxisomeProliferator-Activated
Receptor-Gamma
The master regulator gene of adipogenesis is PPAR-γ, a
member of the nuclear receptor superfamily [15, 102]. Mice
null for PPAR-γ are embryonic lethal [103], suggesting
PPAR-γ is essential for normal mouse development. PPAR-
γ is a ligand-activated transcription factor, whereupon
binding of the ligand, PPAR-γ translocates to the nucleus
and heterodimerizes with RXR [104]. PPAR-γ binds to
the target gene at a PPAR response element (PPRE),
where it initiates transcription through the recruitment of
transcriptional machinery [105]. Loss-of-function and gain-
of-function mutations of PPAR-γ have been implicated in
a number of disease processes, primarily type-2 diabetes
mellitus, or insulin resistant diabetes [106]. The thiazo-
lidinedione (TZD) family of drugs works to activate PPAR-
γ, restoring insulin sensitivity to tissue, upregulating free
fatty acid uptake by adipocytes, and altering expression of
adipokines [107, 108]. PAI-1 expression is known to be
regulated by PPAR-γ, though the literature is conflicting,
suggesting PPAR-γ downregulates PAI-1 expression [109–
111], while others suggests PAI-1 is upregulated by PPAR-
γ agonists [28, 29, 112]. As adipogenesis is regulated
by PPAR-γ, it has been postulated that obesity and the
associated adipocyte pathology is due to a downregulation of
PPAR-γ activity, either through mutation, phosphorylation,
or methylation [113–115]. While PPAR-γ is required for
adipocyte differentiation, under normal conditions, PPAR-
γ serves to regulate cell size and transcription of adipocyte
specific genes [16, 116]. One hallmark of obesity is ele-
vated levels of inflammatory cytokines. In addition to
positively regulating gene transcription, PPAR-γ has been
shown to inhibit gene transcription as well [117, 118].
By blocking gene transcription machinery from binding
the promoter site, PPAR-γ negatively regulates several
genes, including NFκB, a key transcriptional factor involved
in numerous disease processes, including inflammation
[117].
The ability of PPAR-γ to inhibit NF-κB expression is
important in breast cancer progression, since NF-κB has
been shown to increase tumor cell invasiveness as a result
of increased uPA expression [119]. Altered expression of
nuclear NF-κB has also been shown to prevent apopto-
sis [120]. Other studies have shown NF-κB is involved
in mammary epithelial proliferation [121, 122], and also
chemoresistance in MCF-7 breast cancer cells [121]. In
addition to its role in inhibiting NF-κB expression, PPAR-γ
activation has also been shown to downregulate transcrip-
tion of the insulin receptor (IR) by physically interacting
withthetranscription factorsSp1,C/EBPβ,andAP1invitro,
preventing IR transcription [118]. Insulin receptor signaling
has been implicated in a number of neoplastic processes
including proliferation, invasion, and cell survival [123].
Recently, elevated levels of insulin in newly diagnosed breast
cancer patients were shown to be related to an underlying
insulin resistance [124]. These data, and the fact that insulin
resistance is associated with increased risk of breast cancer
[125] and poor patient prognosis [126], suggest a possible
role for PPAR-γ activators in either prevention or treatment
of breast cancer patients.
Since PPAR-γ regulates adipocyte differentiation and
normal function, PPAR-γ malfunction may play a role in
tumor development. Several studies have shown PPAR-γ is
expressed in a variety of tumor types, including pituitary
tumors [127], ovaries [128], prostate [22, 88], colon [129],
and breast [88]. While the in vivo role of PPAR-γ in these
tumor cells is unknown, in vitro data suggests PPAR-γ
activation can induce apoptosis [26] and promote terminal
differentiation of breast tumor cells [88]. Nunez et al.
reported induction of apoptosis in the MDA-MB-231 breast
cancer cell line, but not in normal fibroblasts, treated with
ciglitazone following amino acid deprivation [23]. More
recently, Bonofiglio et al. showed rosiglitazone enhances
FasL expression in a PPAR-γ dependent manner, resulting in
induction of apoptosis in a number of human breast cancer
cell lines [130].
The findings above supported a clinical trial testing
troglitazone as a new chemotherapeutic agent in breast
cancer, which was terminated when troglitazone was taken
off the market for severe liver toxicity [131]. More recent
clinical trials have looked into the chemotherapeutic effects
of two commercially available PPAR-γ agonists. A Phase-
I trial investigating rosiglitazone treatment in conjunction
withbexarotenefoundthemaximumtolerateddoseinbreast
cancer patients with refractory disease [132]. A Phase-II trial
treating patients with high-grade gliomas with combination
therapy of pioglitazone and the COX-2 inhibitor rofecoxib
showed moderate activity, which was tolerated well by the
patients [133]. While these clinical trials showed no overall
improvement, there is evidence to suggest treatment of
diabetic patients with PPAR-γ agonists may have some
preventive effects on cancer development. One study looked
at male type 2 diabetes patients and found patients treated
with TZDs had lower incidences of cancer, specifically lung
cancer [134]. As this study was designed using male patients,
there is no breast cancer data. A metaanalysis of clinical
trial data found patients treated with the TZD rosiglitazone
had lower incidences of malignancy than control non-TZD
treated patients [135]. As the number of patients with type
2 diabetes increases, it will be important to closely monitor
the patients treated with TZDs in terms of incidences of
malignancy.
6.Diet,PPAR-γ, andCancerDevelopment
Recent epidemiologic studies suggest diet may also be
associated with developing certain cancers. In 1997, Huang
et al. showed a positive correspondence to adult weight gain
and postmenopausal development of breast cancer [136].
These results and others suggest obesity is a modifiable risk
factor for breast cancer development. More recently, a study
showed body mass index (BMI) to be correlated with several
sex hormones, helping to explain the positive relationship
between obesity and breast cancer risk [137]. Adult weight
gain has also been associated with an increased risk of breast
cancer, particularly in women not on hormone replacement
therapy [138–140].

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Inadditiontoreportsofobesityandcancerdevelopment,
a number of studies suggest diet is a key player in cancer
progression. Increased fat intake is a risk factor for a number
of cancers, including breast, prostate, and colon. While the
mechanism is not fully understood, dietary fats have been
implicated in tumor progression. Dietary fats, specifically
polyunsaturated fatty acids (PUFAs), are certainly involved
in the inflammatory process [141, 142], which is linked to
cancer cell motility and survival. PUFAs include the omega-
3 (ω-3) and omega-6 (ω-6) classes of dietary fatty acids,
both of which play essential roles in normal physiology.
Interestingly, both ω-3 and ω-6 fatty acids have been shown
to bind and activate PPAR-γ [25, 143–146]. Consumption of
ω-3 fatty acids, specifically, eicosapentanoic acid (EPA) and
docosahexanoic acid (DHA), decrease the risk of coronary
artery disease, stroke, and other diseases associated with an
inflammatory response, such as Crohn’s disease [90, 147,
148]. More recently, ω-3 fatty acids have been shown to
inhibit tumor growth and decrease tumor cell motility [149–
151]. While ω-3 fatty acids are often associated with health
benefits, ω-6 fatty acids have been implicated in a number
of disease processes. The ω-6 PUFA arachidonic acid (AA)
hasbeenshowntoincreasecellmotilityandsurvivalthrough
inactivation of the tumor suppressor PTEN [152], while
another group has shown that AA directly activates PI3K and
upregulates numerous inflammatory genes [153]. Because
AA is an essential fatty acid, it is required for normal cell
homeostasis, suggesting some AA is critical, but excess AA
can be problematic.
Several studies suggest the ω-3 PUFA to ω-6 PUFA ratio
is what drives cancer cell biology. In prostate cancer, cells
with a lower ω-3 to ω-6 ratio had increased cell survival and
motility [154]. It is important to note diets in the United
States typically consist of elevated levels ω-6, compared to
a Mediterranean or Asian diet [91, 155]. Numerous studies
have investigated PPAR-γ activation by dietary fatty acids.
AA has been implicated as a regulator of PPAR-γ activity
as well, downregulating transcription of a PPAR-γ target
gene GLUT4 [146]. Another ω-6 fatty acid gamma-linolenic
acid (GLA) has been shown to activate PPAR-γ in breast
cancer cells, resulting in cytotoxicity and adhesion [156].
One group showed a differential effect of ω-3 versus ω-6
fatty acids on PPAR-γ transcriptional activity [157], with ω-
3 fatty acids downregulating PPAR-γ activity in the MCF-7
breast cancer cell line. It should be noted, numerous studies
suggest ω-3 fatty acids act as PPAR-γ agonists. Sun et al.
showed ω-3 fatty acids increase syndecan-1 production in
breastcancercellsthroughPPAR-γ activation[151].Another
study showed eicosapentaenoic acid (EPA) activates PPAR-γ,
resulting in inhibition of interleukin-6 expression in glioma
cells [158, 159]. Using human colon cancer cell, Allred,
et al. showed EPA suppressed cell growth through PPAR-γ
activation [159].
Increased long-chain ω-6 fatty acids in adipose tissue of
the breast have been shown to correlate with development of
breastcancer[94,95].Tumorsinmicefedincreasedω-3fatty
acids had increased apoptosis and decreased proliferation,
suggesting a protective role of ω-3 fatty acids in tumor
progression [154]. In breast cancer cells, gene expression is
differentially regulated by ω-3 and ω-6 fatty acids [160]. A
number of animal studies also suggest a protective role for
ω-3 fatty acids in breast cancer progression [161]. Recently,
a study showed ω-3 fatty acids inhibits HER-2/neu-induced
breast cancer in transgenic mice, independent of PPAR-γ
activity [162]. Horia and Watkins [163] reported that MDA-
MB-231 cells treated with docosahexanoic acid (DHA) and
genistein were less invasive, had reduced COX-2 and NF-κB
expression and increased PPAR-γ expression. Furthermore,
in vivo, increasing ω-6 fatty acid in mice with prostate
cancerxenograftsresultsinincreasedtumorgrowthandfinal
tumor volumes [154]. Taken together, these studies begin to
explain the role of diet and obesity in breast cancer risk and
development, potentially mediated through PPAR-γ activity.
The importance of the tumor microenvironment must
not be overlooked in cancer research. In recent years,
evidence has increasingly shown the relationship between
tumor cells and the surrounding stromal cells. In prostate
cancer, there are reports of cross-talk between bone and
metastasized prostate carcinoma cells, promoting growth
and survival of metastatic lesions [164]. Adipocytes have
been shown to promote tumor growth by secretion and
processing of collagen IV, which activates AKT signaling
pathway in breast epithelial cells [165]. Using proteomic
analysis of adipocyte cells and interstitial fluid of fat tissue
from the breast, another study identified proteins involved in
metabolism, apoptosis, and immune response [166]. These
studies suggest a link between adipocytes in the breast tissue
and support of tumor development and growth.
In terms of the role of PPAR-γ in cancer-stromal cell
interactions, the literature is both sparse and contradictory.
One in vitro study shows inhibition of adhesion between
multiple myeloma and bone marrow stromal cells, through
reduced activity of both NF-κB and C/EBPb by PPAR-γ
agonists [167], reducing growth and metastasis of multiple
myeloma. Another in vitro study showed stromal cell
expression of prostaglandin D synthase derived products
suppressed prostate tumor growth and that this was medi-
ated through PPAR-γ activation in the tumor cells [168].
Most in vivo characterization of PPAR-γ in tumors has been
done through immunohistochemical analysis, which does
not show activity of PPAR-γ, merely expression. There are
a number of citations showing PPAR-γ protein expression
in tumor samples [88, 127, 129, 169–171], though there is
no definitive explanation for its presence. One study showed
expression of PPAR-γ in pancreatic cancer is correlated with
shorter patient survival [171], while expression of PPAR-γ
incolonadenocarcinomasamplescorrespondedtoincreased
expression of cell-cycle molecules [129]. These results sug-
gest PPAR-γ activation may be used to induce expression
of cell-cycle machinery. Another study found PPAR-γ to
be highly expressed in both primary and metastatic breast
cancer tissue samples [88]. A study in human mammary
ductal carcinoma in situ (DCIS) found elevated expression
of nuclear PPAR-γ was inversely related to disease recurrence
following breast conservation therapy [172]. Suzuki et al.
show PPAR-γ immunoreactivity in breast carcinoma tissue
was associated with improved clinical outcome [173]. While
these studies reveal the presence of PPAR-γ in tumor cells,

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Nucleus
Lipoxygenases,
cyclooxygenases
Diet and
adipose tissue
Breast tumor cell
Prostaglandins,
leukotrienes
RXR
Coactivator
PPARγ
PAI-1
Extravasation from primary
tumor site
Microenvironment supports
proliferation
Promotion of angiogenesis
Aromatase,
( Estrogen),
Leptin,
Adiponectin,
TNF
PAI-1
Cytoplasm
uPA/uPAR
+
Adipose
tissue
Adipose
tissue
ω-6 and ω-3
fatty acids
-α,
Figure 2: Potential Role of PPAR-γ, Fatty Acid Ligands, Adipose Tissue, and the Plasminogen Activator System in Breast Cancer.
without evidence suggesting PPAR-γ activity, one cannot
fully understand the role of PPAR-γ in tumor cell biology in
vivo.
7.Summary
While there is a substantial amount of data on PPAR-γ
pertaining to its role in normal cell function and diabetes,
there is no solid understanding of its function in cancer cell
lines or tumor samples. The in vitro data supports a role
for PPAR-γ in differentiation of tumor cells [88] as well as
induction of apoptosis [174–176], though there is no strong
in vivo data to support the in vitro results. What is known
is that obesity exhibits a number of hallmarks for altered
PPAR-γ function, including dysregulation of adipokine
secretion. In this review, we have presented support for our
hypothesized mechanism of increased breast cancer risk in
obese individuals. With elevated levels of PAI-1 in obese
women, the potential is there for increased proliferation,
decreased apoptosis, and increased cellular migration, all
contributing to tumor development and metastasis in the
breast (Figure 2). The close proximity to a large pool of
adipose tissue in the microenvironment could predispose
obese women to developing breast cancer.
The potential to use PPAR-γ agonists as chemothera-
peutic agents in breast cancer is a very viable option. It is
possible that inducing PPAR-γ activity systemically in the
obese individual could alter PAI-1 expression, resulting in a
less pathogenic phenotype in the breast tissue. Additionally,
by activating PPAR-γ, NF-κB has been shown to be down-
regulated, resulting in reduced uPA expression. Inhibiting
uPA expression also has the potential to alter the breast
tissue microenvironment, preventing possible tumor cells
from invading into the surrounding vasculature. Less toxic
PPAR-γ agonists, such as pioglitazone or rosiglitazone, both
FDA approved and commercially available to treatment of
diabetes,mayprovetobeusefulchemotherapeuticagentsfor
breast cancer patients.
Acknowledgments
Stipend support to the first author was provided by NIEHS
5T32-ES-07017 from the National Institute of Environmen-
tal Health Sciences, and the Sequoyah Fellowship from
the Graduate School, UNC Chapel Hill. This research was
supported in part by Research Grants (BCTR0503475 and
BCTR45206) from the Susan G. Komen Breast Cancer
Foundation to the second author
References
[1] A. Jemal, R. Siegel, E. Ward, et al., “Cancer statistics, 2008,”
CA Cancer Journal for Clinicians, vol. 58, no. 2, pp. 71–96,
2008.
[2] D. Trichopoulos, H.-O. Adami, A. Ekbom, C.-C. Hsieh, and
P. Lagiou, “Early life events and conditions and breast cancer
risk: from epidemiology to etiology,” International Journal of
Cancer, vol. 122, no. 3, pp. 481–485, 2008.
[3] C. J. Anthony, “Risk factors associated with breast cancer,”
Nurse Practitioner, vol. 3, no. 4, pp. 31–32, 1978.
[4] R. B. Wallace, B. M. Sherman, and J. A. Bean, “Men-
strual cycle patterns and breast cancer risk factors,” Cancer
Research, vol. 38, no. 11, pp. 4021–4024, 1978.
[5] C.P.Crum,S.C.Lester,andR.S.Cotran,“Thefemalegenital
systemandbreast,”inRobbinsBasicPathology,V.Kumar,Ed.,
Saunders, Philadelphia, Pa, USA, 2003.
[6] B. Antuna-Puente, B. Feve, S. Fellahi, and J.-P. Bastard,
“Adipokines: the missing link between insulin resistance and
obesity,” Diabetes and Metabolism, vol. 34, no. 1, pp. 2–11,
2008.

Page 8

8PPAR Research
[7] N. F. Boyd, H. Guo, L. J. Martin, et al., “Mammographic
density and the risk and detection of breast cancer,” The New
England Journal of Medicine, vol. 356, no. 3, pp. 227–236,
2007.
[8] N. F. Boyd, L. J. Martin, L. Sun, et al., “Body size, mammo-
graphic density, and breast cancer risk,” Cancer Epidemiology
Biomarkers and Prevention, vol. 15, no. 11, pp. 2086–2092,
2006.
[9] N. F. Boyd, J. M. Rommens, K. Vogt, et al., “Mammographic
breast density as an intermediate phenotype for breast
cancer,” Lancet Oncology, vol. 6, no. 10, pp. 798–808, 2005.
[10] P. S. Steeg, “Invasion and metastasis,” Current Opinion in
Oncology, vol. 4, no. 1, pp. 134–141, 1992.
[11] J. A. Lawrence, P. S. Steeg, and N. C. Institute, “Mechanisms
of tumor invasion and metastasis,” World Journal of Urology,
vol. 14, no. 3, pp. 124–130, 1996.
[12] N. J. MacDonald and P. S. Steeg, “Molecular basis of tumour
metastasis,” Cancer Surveys, vol. 16, pp. 175–199, 1993.
[13] P. A. Andreasen, R. Egelund, and H. H. Petersen, “The
plasminogen activation system in tumor growth, invasion,
and metastasis,” Cellular and Molecular Life Sciences, vol. 57,
no. 1, pp. 25–40, 2000.
[14] A. Knoop, P. A. Andreasen, J. A. Andersen, et al., “Prognostic
significance of urokinase-type plasminogen activator and
plasminogen activator inhibitor-1 in primary breast cancer,”
British Journal of Cancer, vol. 77, no. 6, pp. 932–940, 1998.
[15] P. Tontonoz, E. Hu, and B. M. Spiegelman, “Regulation of
adipocyte gene expression and differentiation by peroxisome
proliferatoractivatedreceptorγ,”CurrentOpinioninGenetics
and Development, vol. 5, no. 5, pp. 571–576, 1995.
[16] E. D. Rosen, P. Sarraf, A. E. Troy, et al., “PPARγ is required
for the differentiation of adipose tissue in vivo and in vitro,”
Molecular Cell, vol. 4, no. 4, pp. 611–617, 1999.
[17] D. Paltoo, K. Woodson, P. Taylor, D. Albanes, J. Virtamo,
and J. Tangrea, “Pro12Ala polymorphism in the peroxisome
proliferator-activated receptor-γ (PPAR-γ) gene and risk of
prostate cancer among men in a large cancer prevention
study,” Cancer Letters, vol. 191, no. 1, pp. 67–74, 2003.
[18] P. Sarraf, E. Mueller, W. M. Smith, et al., “Loss-of-function
mutations in PPARγ associated with human colon cancer,”
Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999.
[19] M.Gurnell,D.B.Savage,V.K.K.Chatterjee,andS.O’Rahilly,
“Themetabolic syndrome:peroxisomeproliferator-activated
receptorγ anditstherapeuticmodulation,”JournalofClinical
Endocrinology and Metabolism, vol. 88, no. 6, pp. 2412–2421,
2003.
[20] M.Gurnell,“PPARγ andmetabolism:insightsfromthestudy
of human genetic variants,” Clinical Endocrinology, vol. 59,
no. 3, pp. 267–277, 2003.
[21] R. P. Brun and B. M. Spiegelman, “PPARγ and the molecular
control of adipogenesis,” Journal of Endocrinology, vol. 155,
no. 2, pp. 217–218, 1997.
[22] D. Nagata, H. Yoshihiro, M. Nakanishi, et al., “Peroxisome
proliferator-activated receptor-γ and growth inhibition by its
ligands in prostate cancer,” Cancer Detection and Prevention,
vol. 32, no. 3, pp. 259–266, 2008.
[23] N. P. Nunez, H. Liu, and G. G. Meadows, “PPAR-γ lig-
ands and amino acid deprivation promote apoptosis of
melanoma, prostate, and breast cancer cells,” Cancer Letters,
vol. 236, no. 1, pp. 133–141, 2006.
[24] J. Liu, H. Lu, R. Huang, et al., “Peroxisome proliferator
activated receptor-γ ligands induced cell growth inhibition
and its influence on matrix metalloproteinase activity in
human myeloid leukemia cells,” Cancer Chemotherapy and
Pharmacology, vol. 56, no. 4, pp. 400–408, 2005.
[25] H. Zand, A. Rhimipour, M. Bakhshayesh, M. Shafiee, I. Nour
Mohammadi, and S. Salimi, “Involvement of PPAR-γ and
p53 in DHA-induced apoptosis in Reh cells,” Molecular and
Cellular Biochemistry, vol. 304, no. 1-2, pp. 71–77, 2007.
[26] T. Takashima, Y. Fujiwara, K. Higuchi, et al., “PPAR-γ
ligandsinhibitgrowthofhumanesophagealadenocarcinoma
cells through induction of apoptosis, cell cycle arrest and
reduction of ornithine decarboxylase activity,” International
Journal of Oncology, vol. 19, no. 3, pp. 465–471, 2001.
[27] H. Sawai, J. Liu, H. A. Reber, O. J. Hines, and G. Eibl,
“Activation of peroxisome proliferator-activated receptor-γ
decreasespancreaticcancercellinvasionthroughmodulation
of the plasminogen activator system,” Molecular Cancer
Research, vol. 4, no. 3, pp. 159–167, 2006.
[28] H.Ihara,T.Urano,A.Takada,andD.J.Loskutoff,“Induction
of plasminogen activator inhibitor 1 gene expression in
adipocytes by thiazolidinediones,” The FASEB Journal, vol.
15, no. 7, pp. 1233–1235, 2001.
[29] Y. Suzuki, T. Urano, H. Ihara, et al., “Bezafibrate attenuates
the overexpression of plasminogen activator inhibitor-1
messengerRNAbyacombinationofmono-unsaturatedfatty
acid and insulin in HepG2 cells,” Life Sciences, vol. 68, no. 16,
pp. 1827–1837, 2001.
[30] J. P. Quigley, M. B. Berkenpas, R. T. Aimes, and J. M.
Chen, “Serine protease and metallo protease cascade systems
involved in pericellular proteolysis,” Cell Differentiation and
Development, vol. 32, no. 3, pp. 263–276, 1990.
[31] M. J. Duffy, “The urokinase plasminogen activator system:
role in malignancy,” Current Pharmaceutical Design, vol. 10,
no. 1, pp. 39–49, 2004.
[32] B.Han,M.Nakamura,I.Mori,Y.Nakamura,andK.Kakudo,
“Urokinase-type plasminogen activator system and breast
cancer (review),” Oncology Reports, vol. 14, no. 1, pp. 105–
112, 2005.
[33] J. Y. Cho, H. C. Chung, S. H. Noh, J. K. Roh, J. S. Min,
and B. S. Kim, “High level of urokinase-type plasminogen
activator is a new prognostic marker in patients with gastric
carcinoma,” Cancer, vol. 79, no. 5, pp. 878–883, 1997.
[34] S. Papadopoulou, A. Scorilas, J. Yotis, et al., “Significance
of urokinase-type plasminogen activator and plasminogen
activator inhibitor-1 (PAI-1) expression in human colorectal
carcinomas,”TumorBiology,vol.23,no.3,pp.170–178,2002.
[35] N. Brunner, C. Pyke, C. H. Hansen, J. Romer, J. Grondahl-
Hansen, and K. Dano, “Urokinase plasminogen activator
(uPA) and its type 1 inhibitor (PAI-1): regulators of prote-
olysis during cancer invasion and prognostic parameters in
breast cancer,” Cancer Treatment and Research, vol. 71, pp.
299–309, 1994.
[36] J. L. Fisher, C. L. Field, H. Zhou, T. L. Harris, M. A.
Henderson, and P. F. M. Choong, “Urokinase plasminogen
activator system gene expression is increased in human
breast carcinoma and its bone metastases—a comparison of
normal breast tissue, non-invasive carcinoma and osseous
metastases,” Breast Cancer Research and Treatment, vol. 61,
no. 1, pp. 1–12, 2000.
[37] D. J. Webb, D. H. D. Nguyen, M. Sankovic, and S. L.
Gonias, “The very low density lipoprotein receptor regulates
urokinase receptor catabolism and breast cancer cell motility
in vitro,” Journal of Biological Chemistry, vol. 274, no. 11, pp.
7412–7420, 1999.

Page 9

PPAR Research9
[38] C.M.HekmanandD.J.Loskutoff,“Endothelialcellsproduce
a latent inhibitor of plasminogen activators that can be
activated by denaturants,” Journal of Biological Chemistry,
vol. 260, no. 21, pp. 11581–11587, 1985.
[39] R. Verloes, G. Atassi, P. Dumont, and L. Kanarek, “Tumor
growthinhibitionmediatedbytrypsininhibitororurokinase
inhibitors,”EuropeanJournalofCancerandClinicalOncology,
vol. 14, no. 1, pp. 23–31, 1978.
[40] I. M. Lang, K. M. Moser, and R. R. Schleef, “Elevated
expression of urokinase-like plasminogen activator and
plasminogen activator inhibitor type 1 during the vascular
remodeling associated with pulmonary thromboembolism,”
Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no.
5, pp. 808–815, 1998.
[41] H. A. Chapman Jr. and O. L. Stone, “Characterization
of a macrophage-derived plasminogen-activator inhibitor.
Similarities with placental urokinase inhibitor,” Biochemical
Journal, vol. 230, no. 1, pp. 109–116, 1985.
[42] M. Jo, K. S. Thomas, N. Marozkina, et al., “Dynamic
assembly of the urokinase-type plasminogen activator sig-
naling receptor complex determines the mitogenic activity of
urokinase-type plasminogen activator,” Journal of Biological
Chemistry, vol. 280, no. 17, pp. 17449–17457, 2005.
[43] C. Holst-Hansen, B. Johannessen, G. Hoyer-Hansen, J.
Romer, V. Ellis, and N. Brunner, “Urokinase-type plas-
minogen activation in three human breast cancer cell lines
correlates with their in vitro invasiveness,” Clinical and
Experimental Metastasis, vol. 14, no. 3, pp. 297–307, 1996.
[44] V. Costantini, A. Sidoni, R. Deveglia, et al., “Combined
overexpression of urokinase, urokinase receptor, and plas-
minogen activator inhibitor-1 is associated with breast
cancer progression: an immunohistochemical comparison of
normal, benign, and malignant breast tissues,” Cancer, vol.
77, no. 6, pp. 1079–1088, 1996.
[45] C.Korninger,O.Wagner,andB.R.Binder,“Tissueplasmino-
gen activator inhibitor in human plasma: development of a
functional assay system and demonstration of a correlating
Mr = 50,000 antiactivator,” Journal of Laboratory and Clinical
Medicine, vol. 105, no. 6, pp. 718–724, 1985.
[46] L. Strandberg, D. Lawrence, and T. Ny, “The organization of
the human-plasminogen-activator-inhibitor-1 gene. Impli-
cations on the evolution of the serine-protease inhibitor
family,” European Journal of Biochemistry, vol. 176, no. 3, pp.
609–616, 1988.
[47] P. W. Bergum and L. A. Erickson, “Neutralization by
plasminogen activator inhibitor-1 of mutants of tissue plas-
minogen activator,” Enzyme, vol. 40, no. 2-3, pp. 122–129,
1988.
[48] C. Masson and E. Angles-Cano, “Kinetic analysis of the
interaction between plasminogen activator inhibitor-1 and
tissue-type plasminogen activator,” Biochemical Journal, vol.
256, no. 1, pp. 237–244, 1988.
[49] T.-C. Wun, M. O. Palmier, N. R. Siegel, and C. E.
Smith, “Affinity purification of active plasminogen activator
inhibitor-1 (PAI-1) using immobilized anhydrourokinase.
Demonstration of the binding, stabilization, and activation
of PAI-1 by vitronectin,” Journal of Biological Chemistry, vol.
264, no. 14, pp. 7862–7868, 1989.
[50] J. A. Foekens, M. P. Look, H. A. Peters, W. L. J. Van Putten, H.
Portengen, and J. G. M. Klijn, “Urokinase-type plasminogen
activator and its inhibitor PAI-1: predictors of poor response
to tamoxifen therapy in recurrent breast cancer,” Journal of
the National Cancer Institute, vol. 87, no. 10, pp. 751–756,
1995.
[51] J. Grondahl-Hansen, I. J. Christensen, C. Rosenquist, et al.,
“High levels of urokinase-type plasminogen activator and its
inhibitor PAI-1 in cytosolic extracts of breast carcinomas are
associated with poor prognosis,” Cancer Research, vol. 53, no.
11, pp. 2513–2521, 1993.
[52] M. Matsuyama and R. Yoshimura, “Peroxisome proliferator-
activated receptor-γ is a potent target for prevention and
treatment in human prostate and testicular cancer,” PPAR
Research, vol. 2008, Article ID 249849, 2008.
[53] K. Bajou, J.-M. Lewalle, C. R. Martinez, et al., “Human
breast adenocarcinoma cell lines promote angiogenesis by
providing cells with uPA-PAI-1 and by enhancing their
expression,” International Journal of Cancer, vol. 100, no. 5,
pp. 501–506, 2002.
[54] S. B. Fox, M. Taylor, J. Grondahl-Hansen, S. Kakolyris, K. C.
Gatter, and A. L. Harris, “Plasminogen activator inhibitor-
1 as a measure of vascular remodelling in breast cancer,”
Journal of Pathology, vol. 195, no. 2, pp. 236–243, 2001.
[55] D. Palmieri, J. W. Lee, R. L. Juliano, and F. C. Church,
“Plasminogen activator inhibitor-1 and -3 increase cell
adhesion and motility of MDA-MB-435 breast cancer cells,”
Journal of Biological Chemistry, vol. 277, no. 43, pp. 40950–
40957, 2002.
[56] B. Chazaud, R. Ricoux, C. Christov, A. Plonquet, R. K.
Gherardi, and G. Barlovatz-Meimon, “Promigratory effect of
plasminogen activator inhibitor-1 on invasive breast cancer
cell populations,” American Journal of Pathology, vol. 160, no.
1, pp. 237–246, 2002.
[57] I. Martens, D. Ballaux, T. Funahashi, et al., “Inverse relation-
ship between plasminogen activator inhibitor-I activity and
adiponectin in overweight and obese women. Interrelation-
ship with visceral adipose tissue, insulin resistance, HDL-
chol and inflammation,” Thrombosis and Haemostasis, vol.
94, no. 6, pp. 1190–1195, 2005.
[58] Y. Chen, R. C. Budd, R. J. Kelm Jr., B. E. Sobel, and
D. J. Schneider, “Augmentation of proliferation of vascular
smooth muscle cells by plasminogen activator inhibitor type
1,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26,
no. 8, pp. 1777–1783, 2006.
[59] T. You, R. Yang, M. F. Lyles, D. Gong, and B. J. Nicklas,
“Abdominal adipose tissue cytokine gene expression: rela-
tionship to obesity and metabolic risk factors,” American
Journal of Physiology, vol. 288, no. 4, pp. E741–E747, 2005.
[60] M.-C. Alessi, D. Bastelica, P. Morange, et al., “Plasminogen
activator inhibitor 1, transforming growth factor-β1, and
BMI are closely associated in human adipose tissue during
morbid obesity,” Diabetes, vol. 49, no. 8, pp. 1374–1380,
2000.
[61] F. Samad, K. T. Uysal, S. M. Wiesbrock, M. Pandey, G. S.
Hotamisligil, and D. J. Loskutoff, “Tumor necrosis factor α
is a key component in the obesity-linked elevation of plas-
minogen activator inhibitor 1,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 96,
no. 12, pp. 6902–6907, 1999.
[62] F. Samad, J. Schneiderman, and D. Loskutoff, “Expression
of fibrinolytic genes in tissues from human atherosclerotic
aneurysms and from obese mice,” Annals of the New York
Academy of Sciences, vol. 811, pp. 350–360, 1997.
[63] F. Samad and D. J. Loskutoff, “Tissue distribution and
regulation of plasminogen activator inhibitor-1 in obese
mice,” Molecular Medicine, vol. 2, no. 5, pp. 568–582, 1996.
[64] B. Wang, J. R. Jenkins, and P. Trayhurn, “Expression and
secretion of inflammation-related adipokines by human

Page 10

10PPAR Research
adipocytes differentiated in culture: integrated response to
TNF-α,” American Journal of Physiology, vol. 288, no. 4, pp.
E731–E740, 2005.
[65] K. Sakamoto, T. Sakamoto, and H. Ogawa, “Effects of
metabolic risk factors on production of plasminogen activa-
tor inhibitor-1 and adiponectin by adipocytes,” Circulation
Journal, vol. 72, no. 5, pp. 844–846, 2008.
[66] A. R. Carmichael, “Obesity as a risk factor for development
and poor prognosis of breast cancer,” BJOG, vol. 113, no. 10,
pp. 1160–1166, 2006.
[67] A. Trentham-Dietz, P. A. Newcomb, H. B. Nichols, and
J. M. Hampton, “Breast cancer risk factors and second
primary malignancies among women with breast cancer,”
Breast Cancer Research and Treatment, vol. 105, no. 2, pp.
195–207, 2007.
[68] L. Gallicchio, M. A. McSorley, C. J. Newschaffer, et al., “Body
mass, polymorphisms in obesity-related genes, and the risk
of developing breast cancer among women with benign
breast disease,” Cancer Detection and Prevention, vol. 31, no.
2, pp. 95–101, 2007.
[69] B.J.Caan,M.L.Kwan,G.Hartzell,etal.,“Pre-diagnosisbody
mass index, post-diagnosis weight change, and prognosis
among women with early stage breast cancer,” Cancer Causes
and Control, vol. 19, no. 10, pp. 1319–1328, 2008.
[70] K. Hede, “Fat may fuel breast cancer growth,” Journal of the
National Cancer Institute, vol. 100, no. 5, pp. 298–299, 2008.
[71] S. D. Hursting, L. M. Lashinger, K. W. Wheatley, et al.,
“Reducing the weight of cancer: mechanistic targets for
breaking the obesity-carcinogenesis link,” Best Practice and
Research: Clinical Endocrinology and Metabolism, vol. 22, no.
4, pp. 659–669, 2008.
[72] J. P. Bastard and L. Pi´ eroni, “Plasma plasminogen acti-
vator inhibitor 1, insulin resistance and android obesity,”
Biomedicine and Pharmacotherapy, vol. 53, no. 10, pp. 455–
461, 1999.
[73] H. C. Kwaan, J. Wang, K. Svoboda, and P. J. Declerck,
“Plasminogen activator inhibitor 1 may promote tumour
growth through inhibition of apoptosis,” British Journal of
Cancer, vol. 82, no. 10, pp. 1702–1708, 2000.
[74] E. A. Torre and R. A. Fulco, “Tumor-associated urokinase-
type plasminogen activator: significance in breast cancer,”
European Journal of Gynaecological Oncology, vol. 17, no. 4,
pp. 315–318, 1996.
[75] T. Ueno, M. Toi, H. Saji, et al., “Significance of macrophage
chemoattractant protein-1 in macrophage recruitment,
angiogenesis, and survival in human breast cancer,” Clinical
Cancer Research, vol. 6, no. 8, pp. 3282–3289, 2000.
[76] S. E. Bulun and E. R. Simpson, “Breast cancer and expression
of aromatase in breast adipose tissue,” Trends in Endocrinol-
ogy and Metabolism, vol. 5, no. 3, pp. 113–120, 1994.
[77] K. J. McInnes, K. A. Brown, K. C. Knower, A. L. Chand, C.
D. Clyne, and E. R. Simpson, “Characterisation of aromatase
expression in the human adipocyte cell line SGBS,” Breast
Cancer Research and Treatment, vol. 112, no. 3, pp. 429–435,
2008.
[78] S. E. Bulun, M. S. Mahendroo, and E. R. Simpson, “Aro-
matase gene expression in adipose tissue: relationship to
breast cancer,” Journal of Steroid Biochemistry and Molecular
Biology, vol. 49, pp. 319–326, 1994.
[79] Y. Miki, T. Suzuki, and H. Sasano, “Controversies of aro-
matase localization in human breast cancer-stromal versus
parenchymal cells,” Journal of Steroid Biochemistry and
Molecular Biology, vol. 106, no. 1–5, pp. 97–101, 2007.
[80] M. E. Grossmann, A. Ray, S. Dogan, N. K. Mizuno, and M. P.
Cleary, “Balance of adiponectin and leptin modulates breast
cancer cell growth,” Cell Research, vol. 18, no. 11, pp. 1154–
1156, 2008.
[81] C. N. Perera, H. G. Chin, N. Duru, and I. G. Camarillo,
“Leptin-regulated gene expression in MCF-7 breast cancer
cells: mechanistic insights into leptin-regulated mammary
tumor growth and progression,” Journal of Endocrinology,
vol. 199, no. 2, pp. 221–233, 2008.
[82] M. Eriksson, O. Johnson, K. Boman, et al., “Improved
fibrinolytic activity during exercise may be an effect of
the adipocyte-derived hormones leptin and adiponectin,”
Thrombosis Research, vol. 122, no. 5, pp. 701–708, 2008.
[83] R. M. E. Blumer, C. P. van Roomen, A. J. Meijer, J. H.
Houben-Weerts, H. P. Sauerwein, and P. F. Dubbelhuis,
“Regulation of adiponectin secretion by insulin and amino
acids in 3T3-L1 adipocytes,” Metabolism, vol. 57, no. 12, pp.
1655–1662, 2008.
[84] T. E. Wade, A. Mathur, D. Lu, D. A. Swartz-Basile, H. A. Pitt,
and N. J. Zyromski, “Adiponectin receptor-1 expression is
decreased in the pancreas of obese mice,” Journal of Surgical
Research, vol. 154, no. 1, pp. 78–84, 2009.
[85] Y. Wang, K. S. L. Lam, and A. Xu, “Adiponectin as a negative
regulator in obesity-related mammary carcinogenesis,” Cell
Research, vol. 17, no. 4, pp. 280–282, 2007.
[86] L. B. Tanko, A. Siddiq, C. Lecoeur, et al., “ACDC/adiponectin
and PPAR-γ gene polymorphisms: implications for features
of obesity,” Obesity Research, vol. 13, no. 12, pp. 2113–2121,
2005.
[87] B. M. Spiegelman, “PPAR-γ: adipogenic regulator and thia-
zolidinedione receptor,” Diabetes, vol. 47, no. 4, pp. 507–514,
1998.
[88] E. Mueller, P. Sarraf, P. Tontonoz, et al., “Terminal differen-
tiation of human breast cancer through PPARγ,” Molecular
Cell, vol. 1, no. 3, pp. 465–470, 1998.
[89] M. H. Fenner and E. Elstner, “Peroxisome proliferator-
activated receptor-γ ligands for the treatment of breast
cancer,” Expert Opinion on Investigational Drugs, vol. 14, no.
6, pp. 557–568, 2005.
[90] A. P. Simopoulos, “The importance of the omega-6/omega-
3 fatty acid ratio in cardiovascular disease and other chronic
diseases,” Experimental Biology and Medicine, vol. 233, no. 6,
pp. 674–688, 2008.
[91] A. P. Simopoulos, “Evolutionary aspects of diet, the omega-
6/omega-3 ratio and genetic variation: nutritional implica-
tions for chronic diseases,” Biomedicine and Pharmacother-
apy, vol. 60, no. 9, pp. 502–507, 2006.
[92] I. M. Berquin, I. J. Edwards, and Y. Q. Chen, “Multi-targeted
therapy of cancer by omega-3 fatty acids,” Cancer Letters, vol.
269, no. 2, pp. 363–377, 2008.
[93] B. A. Stoll, “n-3 fatty acids and lipid peroxidation in breast
cancer inhibition,” British Journal of Nutrition, vol. 87, no. 3,
pp. 193–198, 2002.
[94] D. Bagga, K. H. Anders, H.-J. Wang, and J. A. Glaspy, “Long-
chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast
adipose tissue from women with and without breast cancer,”
Nutrition and Cancer, vol. 42, no. 2, pp. 180–185, 2002.
[95] V. Maillard, P. Bougnoux, P. Ferrari, et al., “n-3 and n-6 fatty
acids inbreastadiposetissueandrelativeriskofbreastcancer
inacase-controlstudyintours,France,”InternationalJournal
of Cancer, vol. 98, no. 1, pp. 78–83, 2002.

Page 11

PPAR Research 11
[96] J. N. Fain, A. K. Madan, M. L. Hiler, P. Cheema, and
S. W. Bahouth, “Comparison of the release of adipokines
by adipose tissue, adipose tissue matrix, and adipocytes
from visceral and subcutaneous abdominal adipose tissues
of obese humans,” Endocrinology, vol. 145, no. 5, pp. 2273–
2282, 2004.
[97] K. Blouin, M. Nadeau, J. Mailloux, et al., “Pathways of
adipose tissue androgen metabolism in women: depot differ-
ences and modulation by adipogenesis,” American Journal of
Physiology, vol. 296, no. 2, pp. E244–E255, 2009.
[98] M. Maffei, J. Halaas, E. Ravussin, et al., “Leptin levels
in human and rodent: measurement of plasma leptin and
ob RNA in obese and weight-reduced subjects,” Nature
Medicine, vol. 1, no. 11, pp. 1155–1161, 1995.
[99] Y. Yamazaki, Y. Kawano, and M. Uebayasi, “Induction
of adiponectin by natural and synthetic phenolamides in
mouse and human preadipocytes and its enhancement by
docosahexaenoicacid,”LifeSciences,vol.82,no.5-6,pp.290–
300, 2008.
[100] J. Venugopal, K. Hanashiro, and Y. Nagamine, “Regulation
of PAI-1 gene expression during adipogenesis,” Journal of
Cellular Biochemistry, vol. 101, no. 2, pp. 369–380, 2007.
[101] L. Bahia, L. G. Aguiar, N. Villela, et al., “Relationship
between adipokines, inflammation, and vascular reactivity in
lean controls and obese subjects with metabolic syndrome,”
Clinics, vol. 61, no. 5, pp. 433–440, 2006.
[102] P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B.
M. Spiegelman, “mPPARγ2: tissue-specific regulator of an
adipocyte enhancer,” Genes and Development, vol. 8, no. 10,
pp. 1224–1234, 1994.
[103] Y. Barak, M. C. Nelson, E. S. Ong, et al., “PPARγ is required
for placental, cardiac, and adipose tissue development,”
Molecular Cell, vol. 4, no. 4, pp. 585–595, 1999.
[104] J. Auwerx, G. Martin, M. Guerre-Millo, and B. Staels, “Tran-
scription, adipocyte differentiation, and obesity,” Journal of
Molecular Medicine, vol. 74, no. 7, pp. 347–352, 1996.
[105] P. Tontonoz, E. Hu, and B. M. Spiegelman, “Regulation of
adipocyte gene expression and differentiation by peroxisome
proliferatoractivatedreceptorγ,”CurrentOpinioninGenetics
and Development, vol. 5, no. 5, pp. 571–576, 1995.
[106] S. Heikkinen, J. Auwerx, and C. A. Argmann, “PPARγ in
human and mouse physiology,” Biochimica et Biophysica
Acta, vol. 1771, no. 8, pp. 999–1013, 2007.
[107] C. E. Quinn, P. K. Hamilton, C. J. Lockhart, and G. E.
McVeigh, “Thiazolidinediones: effects on insulin resistance
and the cardiovascular system,” British Journal of Pharmacol-
ogy, vol. 153, no. 4, pp. 636–645, 2008.
[108] R. Dolezalova, M. M. Haluzik, L. Bosanska, et al., “Effect
of PPAR-γ agonist treatment on markers of endothelial
dysfunction in patients with type 2 diabetes mellitus,”
Physiological Research, vol. 56, no. 6, pp. 741–748, 2007.
[109] R. L. C. Hoo, W. S. Chow, M. H. Yau, et al., “Adiponectin
mediates the suppressive effect of rosiglitazone on plas-
minogen activator inhibitor-1 production,” Arteriosclerosis,
Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2777–
2782, 2007.
[110] M. Igarashi, A. Hirata, H. Yamaguchi, Y. Jimbu, and M.
Tominaga, “Pioglitazone reduces atherogenic outcomes in
type 2 diabetic patients,” Journal of Atherosclerosis and
Thrombosis, vol. 15, no. 1, pp. 34–40, 2008.
[111] H. Shimizu, S. Oh-I, T. Tsuchiya, K.-I. Ohtani, S. Okada,
and M. Mori, “Pioglitazone increases circulating adiponectin
levels and subsequently reduces TNF-α levels in type 2
diabetic patients: a randomized study,” Diabetic Medicine,
vol. 23, no. 3, pp. 253–257, 2006.
[112] A. Galli, E. Ceni, D. W. Crabb, et al., “Antidiabetic thiazo-
lidinedionesinhibitinvasivenessofpancreaticcancercellsvia
PPARγ independent mechanisms,” Gut, vol. 53, no. 11, pp.
1688–1697, 2004.
[113] I. Takada, M. Mihara, M. Suzawa, et al., “A histone lysine
methyltransferase activated by non-canonical Wnt signalling
suppresses PPAR-γ transactivation,” Nature Cell Biology, vol.
9, no. 11, pp. 1273–1285, 2007.
[114] B. Relic, V. Benoit, N. Franchimont, et al., “Peroxisome
proliferator-activated receptor-γ1 is dephosphorylated and
degraded during BAY 11-7085-induced synovial fibroblast
apoptosis,” Journal of Biological Chemistry, vol. 281, no. 32,
pp. 22597–22604, 2006.
[115] J. Han, D. P. Hajjar, J. M. Tauras, J. Feng, A. M. Gotto
Jr., and A. C. Nicholson, “Transforming growth factor-β1
(TGF-β1) and TGF-β2 decrease expression of CD36, the
typeBscavengerreceptor,throughmitogen-activatedprotein
kinase phosphorylation of peroxisome proliferator-activated
receptor-γ,” Journal of Biological Chemistry, vol. 275, no. 2,
pp. 1241–1246, 2000.
[116] B.M.Spiegelman,E.Hu,J.B.Kim,andR.Brun,“PPARγ and
the control of adipogenesis,” Biochimie, vol. 79, no. 2-3, pp.
111–112, 1997.
[117] M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K.
Glass, “The peroxisome proliferator-activated receptor-γ is
a negative regulator of macrophage activation,” Nature, vol.
391, no. 6662, pp. 79–82, 1998.
[118] V. Costa, D. Foti, F. Paonessa, et al., “The insulin receptor:
a new anticancer target for peroxisome proliferator-activated
receptor-γ (PPARγ)andthiazolidinedione-PPARγ agonists,”
Endocrine-Related Cancer, vol. 15, no. 1, pp. 325–335, 2008.
[119] D. Sliva, M. T. Rizzo, and D. English, “Phosphatidylinositol
3-kinase and NF-κB regulate motility of invasive MDA-MB-
231 human breast cancer cells by the secretion of urokinase-
type plasminogen activator,” Journal of Biological Chemistry,
vol. 277, no. 5, pp. 3150–3157, 2002.
[120] R. Shao, D. Karunagaran, B. P. Zhou, et al., “Inhibition
of nuclear factor-κB activity is involved in E1A mediated
sensitization of radiation-induced apoptosis,” Journal of
BiologicalChemistry,vol.272,no.52,pp.32739–32742,1997.
[121] C. B. Weldon, M. E. Burow, K. W. Rolfe, J. L. Clayton, B. M.
Jaffe, and B. S. Beckman, “NF-κB-mediated chemoresistance
in breast cancer cells,” Surgery, vol. 130, no. 2, pp. 143–150,
2001.
[122] D. M. Brantley, C.-L. Chen, R. S. Muraoka, et al., “Nuclear
factor-κB (NF-κB) regulates proliferation and branching in
mouse mammary epithelium,” Molecular Biology of the Cell,
vol. 12, no. 5, pp. 1445–1455, 2001.
[123] M. Pollak, “Insulin and insulin-like growth factor signalling
in neoplasia,” Nature Reviews Cancer, vol. 8, no. 12, pp. 915–
928, 2008.
[124] P. J. Goodwin, M. Ennis, M. Bahl, et al., “High insulin levels
in newly diagnosed breast cancer patients reflect underlying
insulin resistance and are associated with components of
the insulin resistance syndrome,” Breast Cancer Research and
Treatment, vol. 114, no. 3, pp. 517–525, 2009.
[125] K.B.Michels,C.G.Solomon,F.B.Hu,etal.,“Type2diabetes
and subsequent incidence of breast cancer in the nurses’
health study,” Diabetes Care, vol. 26, no. 6, pp. 1752–1758,
2003.
[126] M. J. Borugian, S. B. Sheps, C. Kim-Sing, et al., “Insulin,
macronutrient intake, and physical activity: are potential

Page 12

12PPAR Research
indicators of insulin resistance associated with mortality
from breast cancer?” Cancer Epidemiology Biomarkers and
Prevention, vol. 13, no. 7, pp. 1163–1172, 2004.
[127] M. N. Emery, C. Leontiou, S. E. Bonner, et al., “PPAR-γ
expression in pituitary tumours and the functional activity
of the glitazones: evidence that any anti-proliferative effect
of the glitazones is independent of the PPAR-γ receptor,”
Clinical Endocrinology, vol. 65, no. 3, pp. 389–395, 2006.
[128] S. Vignati, V. Albertini, A. Rinaldi, et al., “Cellular and
molecularconsequencesofperoxisomeproliferator-activated
receptor-γ activation in ovarian cancer cells,” Neoplasia, vol.
8, no. 10, pp. 851–861, 2006.
[129] S. Theocharis, C. Giaginis, A. Parasi, et al., “Expression of
peroxisomeproliferator-activatedreceptor-γ incoloncancer:
correlation with histopathological parameters, cell cycle-
related molecules, and patients’ survival,” Digestive Diseases
and Sciences, vol. 52, no. 9, pp. 2305–2311, 2007.
[130] D. Bonofiglio, S. Gabriele, S. Aquila, et al., “Peroxisome
proliferator-activated receptor γ activates fas ligand gene
promoter inducing apoptosis in human breast cancer cells,”
Breast Cancer Research and Treatment, vol. 113, no. 3, pp.
423–434, 2009.
[131] H. J. Burstein, G. D. Demetri, E. Mueller, P. Sarraf, B.
M. Spiegelman, and E. P. Winer, “Use of the peroxisome
proliferator-activated receptor (PPAR) γ ligand troglitazone
as treatment for refractory breast cancer: a phase II study,”
Breast Cancer Research and Treatment, vol. 79, no. 3, pp. 391–
397, 2003.
[132] W. L. Read, M. Q. Baggstrom, P. M. Fracasso, and R.
Govindan, “A phase I study of bexarotene and rosiglitazone
in patients with refractory cancers,” Chemotherapy, vol. 54,
no. 3, pp. 236–241, 2008.
[133] P. Hau, L. Kunz-Schughart, U. Bogdahn, et al., “Low-dose
chemotherapy in combination with COX-2 inhibitors and
PPAR-γ agonists in recurrent high-grade gliomas—a phase
II study,” Oncology, vol. 73, no. 1-2, pp. 21–25, 2008.
[134] R. Govindarajan, L. Ratnasinghe, D. L. Simmons, et al.,
“Thiazolidinediones and the risk of lung, prostate, and colon
cancerinpatientswithdiabetes,”JournalofClinicalOncology,
vol. 25, no. 12, pp. 1476–1481, 2007.
[135] M. Monami, C. Lamanna, N. Marchionni, and E. Mannucci,
“Rosiglitazoneandriskofcancer:ameta-analysisofrandom-
ized clinical trials,” Diabetes Care, vol. 31, no. 7, pp. 1455–
1460, 2008.
[136] Z. Huang, S. E. Hankinson, G. A. Colditz, et al., “Dual effects
of weight and weight gain on breast cancer risk,” Journal of
the American Medical Association, vol. 278, no. 17, pp. 1407–
1411, 1997.
[137] L. M. Morimoto, E. White, Z. Chen, et al., “Obesity, body
size, and risk of postmenopausal breast cancer: the women’s
health initiative (United States),” Cancer Causes and Control,
vol. 13, no. 8, pp. 741–751, 2002.
[138] R. J. Cleveland, S. M. Eng, P. E. Abrahamson, et al., “Weight
gain prior to diagnosis and survival from breast cancer,”
Cancer Epidemiology Biomarkers and Prevention, vol. 16, no.
9, pp. 1803–1811, 2007.
[139] J. Ahn, A. Schatzkin, J. V. Lacey Jr., et al., “Adiposity, adult
weight change, and postmenopausal breast cancer risk,”
Archives of Internal Medicine, vol. 167, no. 19, pp. 2091–2102,
2007.
[140] A. H. Eliassen, G. A. Colditz, B. Rosner, W. C. Willett,
and S. E. Hankinson, “Adult weight change and risk of
postmenopausal breast cancer,” Journal of the American
Medical Association, vol. 296, no. 2, pp. 193–201, 2006.
[141] H. Poirier, J. S. Shapiro, R. J. Kim, and M. A. Lazar, “Nutri-
tional supplementation with trans-10, cis-12-conjugated
linoleic acid induces inflammation of white adipose tissue,”
Diabetes, vol. 55, no. 6, pp. 1634–1641, 2006.
[142] P. C. LaRosa, J. Miner, Y. Xia, Y. Zhou, S. Kachman, and M.
E. Fromm, “Trans-10, cis-12 conjugated linoleic acid causes
inflammation and delipidation of white adipose tissue in
mice: a microarray and histological analysis,” Physiological
Genomics, vol. 27, no. 3, pp. 282–294, 2006.
[143] W. G. Jiang, A. Redfern, R. P. Bryce, and R. E. Mansel, “Per-
oxisome proliferator activated receptor-γ (PPAR-γ) mediates
the action of γ linolenic acid in breast cancer cells,”
Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 62,
no. 2, pp. 119–127, 2000.
[144] D. Shao, S. M. Rangwala, S. T. Bailey, S. L. Krakow, M. J.
Reginato, and M. A. Lazar, “Interdomain communication
regulating ligand binding by PPAR-γ,” Nature, vol. 396, no.
6709, pp. 377–380, 1998.
[145] H. Li, X. Z. Ruan, S. H. Powis, et al., “EPA and DHA reduce
LPS-inducedinflammationresponsesinHK-2cells:evidence
for a PPAR-γ-dependent mechanism,” Kidney International,
vol. 67, no. 3, pp. 867–874, 2005.
[146] M. Armoni, C. Harel, F. Bar-Yoseph, S. Milo, and E. Karnieli,
“Free fatty acids repress the GLUT4 gene expression in
cardiac muscle via novel response elements,” Journal of
BiologicalChemistry,vol.280,no.41,pp.34786–34795,2005.
[147] S. Sierra, F. Lara-Villoslada, M. Comalada, M. Olivares, and
J. Xaus, “Dietary fish oil n-3 fatty acids increase regulatory
cytokine production and exert anti-inflammatory effects in
two murine models of inflammation,” Lipids, vol. 41, no. 12,
pp. 1115–1125, 2006.
[148] P. C. Calder, “n-3 polyunsaturated fatty acids and inflamma-
tion:frommolecularbiologytotheclinic,”Lipids,vol.38,no.
4, pp. 343–352, 2003.
[149] M. D. Brown, C. A. Hart, E. Gazi, S. Bagley, and N.
W. Clarke, “Promotion of prostatic metastatic migration
towards human bone marrow stoma by omega 6 and its
inhibition by omega 3 PUFAs,” British Journal of Cancer, vol.
94, no. 6, pp. 842–853, 2006.
[150] F. Zapata-Gonzalez, F. Rueda, J. Petriz, et al., “Human
dendritic cell activities are modulated by the omega-3 fatty
acid, docosahexaenoic acid, mainly through PPARγ: RXR
heterodimers: comparison with other polyunsaturated fatty
acids,” Journal of Leukocyte Biology, vol. 84, no. 4, pp. 1172–
1182, 2008.
[151] H. Sun, I. M. Berquin, R. T. Owens, J. T. O’Flaherty, and
I. J. Edwards, “Peroxisome proliferator-activated receptor γ-
mediated up-regulation of syndecan-1 by n-3 fatty acids
promotes apoptosis of human breast cancer cells,” Cancer
Research, vol. 68, no. 8, pp. 2912–2919, 2008.
[152] T. M. Covey, K. Edes, and F. A. Fitzpatrick, “Akt activation
by arachidonic acid metabolism occurs via oxidation and
inactivation of PTEN tumor suppressor,” Oncogene, vol. 26,
no. 39, pp. 5784–5792, 2007.
[153] M. Hughes-Fulford, C.-F. Li, J. Boonyaratanakornkit, and
S. Sayyah, “Arachidonic acid activates phosphatidylinositol
3-kinase signaling and induces gene expression in prostate
cancer,” Cancer Research, vol. 66, no. 3, pp. 1427–1433, 2006.
[154] U. P. Kelavkar, J. Hutzley, R. Dhir, P. Kim, K. G. D. Allen,
and K. McHugh, “Prostate tumor growth and recurrence can
be modulated by the omega-6:omega-3 ratio in diet: athymic
mouse xenograft model simulating radical prostatectomy,”
Neoplasia, vol. 8, no. 2, pp. 112–124, 2006.

Page 13

PPAR Research 13
[155] A. P. Simopoulos, “The importance of the ratio of omega-
6/omega-3 essential fatty acids,” Biomedicine and Pharma-
cotherapy, vol. 56, no. 8, pp. 365–379, 2002.
[156] W. G. Jiang, A. Redfern, R. P. Bryce, and R. E. Mansel, “Per-
oxisome proliferator activated receptor-γ (PPAR-γ) mediates
the action of γ linolenic acid in breast cancer cells,”
Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 62,
no. 2, pp. 119–127, 2000.
[157] S. R. Thoennes, P. L. Tate, T. M. Price, and M. W.
Kilgore, “Differential transcriptional activation of peroxi-
some proliferator-activated receptor gamma by omega-3 and
omega-6 fatty acids in MCF-7 cells,” Molecular and Cellular
Endocrinology, vol. 160, no. 1-2, pp. 67–73, 2000.
[158] A. Kawashima, T. Harada, K. Imada, T. Yano, and K.
Mizuguchi, “Eicosapentaenoic acid inhibits interleukin-
6 production in interleukin-1β-stimulated C6 glioma
cells through peroxisome proliferator-activated receptor-γ,”
Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 79,
no. 1-2, pp. 59–65, 2008.
[159] C. D. Allred, D. R. Talbert, R. C. Southard, X. Wang,
and M. W. Kilgore, “PPARγ1 as a molecular target of
eicosapentaenoic acid in human colon cancer (HT-29) cells,”
Journal of Nutrition, vol. 138, no. 2, pp. 250–256, 2008.
[160] R. Hammamieh, N. Chakraborty, S.-A. Miller, et al., “Dif-
ferential effects of omega-3 and omega-6 fatty acids on gene
expression in breast cancer cells,” Breast Cancer Research and
Treatment, vol. 101, no. 1, pp. 7–16, 2007.
[161] D. P. Rose, M. A. Hatala, J. M. Connolly, and J. Rayburn,
“Effect of diets containing different levels of linoleic acid on
human breast cancer growth and lung metastasis in nude
mice,” Cancer Research, vol. 53, no. 18, pp. 4686–4690, 1993.
[162] L. D. Yee, D. C. Young, T. J. Rosol, A. M. VanBuskirk, and S.
K.Clinton,“Dietary(n-3)polyunsaturatedfattyacidsinhibit
HER-2/neu-induced breast cancer in mice independently of
the PPARγ ligand rosiglitazone,” Journal of Nutrition, vol.
135, no. 5, pp. 983–988, 2005.
[163] E. Horia and B. A. Watkin, “Complementary actions of
docosahexaenoic acid and genistein on COX-2, PGE2 and
invasiveness in MDA-MB-231 breast cancer cells,” Carcino-
genesis, vol. 28, no. 4, pp. 809–815, 2007.
[164] A. Angelucci, S. Garofalo, S. Speca, et al., “Arachidonic acid
modulates the crosstalk between prostate carcinoma and
bone stromal cells,” Endocrine-Related Cancer, vol. 15, no. 1,
pp. 91–100, 2008.
[165] P. Iyengar, V. Espina, T. W. Williams, et al., “Adipocyte-
derived collagen VI affects early mammary tumor pro-
gression in vivo, demonstrating a critical interaction in
the tumor/stroma microenvironment,” Journal of Clinical
Investigation, vol. 115, no. 5, pp. 1163–1176, 2005.
[166] J. E. Celis, J. M. A. Moreira, T. Cabezon, et al., “Identification
of extracellular and intracellular signaling components of
the mammary adipose tissue and its interstitial fluid in high
risk breast cancer patients: toward dissecting the molecular
circuitry of epithelial-adipocyte stromal cell interactions,”
Molecular and Cellular Proteomics, vol. 4, no. 4, pp. 492–522,
2005.
[167] L. H. Wang, X. Y. Yang, X. Zhang, and W. L. Farrar, “Inhibi-
tion of adhesive interaction between multiple myeloma and
bone marrow stromal cells by PPARγ cross talk with NF-κB
and C/EBPβ,” Blood, vol. 110, no. 13, pp. 4373–4384, 2007.
[168] J. Kim, P. Yang, M. Suraokar, et al., “Suppression of prostate
tumor cell growth by stromal cell prostaglandin D synthase-
derived products,” Cancer Research, vol. 65, no. 14, pp. 6189–
6198, 2005.
[169] G. P. Vandoros, P. A. Konstantinopoulos, G. Sotiropoulou-
Bonikou, et al., “PPAR-γ is expressed and NF-κB pathway
is activated and correlates positively with COX-2 expression
in stromal myofibroblasts surrounding colon adenocarcino-
mas,” Journal of Cancer Research and Clinical Oncology, vol.
132, no. 2, pp. 76–84, 2006.
[170] H. J. Kim, J.-Y. Hwang, H. J. Kim, et al., “Expression of a
peroxisome proliferator-activated receptor γ1 splice variant
that was identified in human lung cancers suppresses cell
death induced by cisplatin and oxidative stress,” Clinical
Cancer Research, vol. 13, no. 9, pp. 2577–2583, 2007.
[171] G.Kristiansen,J.Jacob,A.-C.Buckendahl,etal.,“Peroxisome
proliferator-activated receptor γ is highly expressed in pan-
creatic cancer and is associated with shorter overall survival
times,” Clinical Cancer Research, vol. 12, no. 21, pp. 6444–
6451, 2006.
[172] S. Kulkarni, D. B. Patil, L. K. Diaz, E. L. Wiley, M. Morrow,
and S. A. Khan, “COX-2 and PPARγ expression are potential
markers of recurrence risk in mammary duct carcinoma in-
situ,” BMC Cancer, vol. 8, article 36, 2008.
[173] T. Suzuki, S. Hayashi, Y. Miki, et al., “Peroxisome
proliferator-activated receptor γ in human breast carcinoma:
a modulator of estrogenic actions,” Endocrine-Related Can-
cer, vol. 13, no. 1, pp. 233–250, 2006.
[174] J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps,
“Peroxisome proliferator activator receptor-γ agonists and
15-deoxy-delta(12,14)(12,14)-PGJ(2) induce apoptosis in
normal and malignant B-lineage cells,” Journal of Immunol-
ogy, vol. 165, no. 12, pp. 6941–6948, 2000.
[175] J. A. Keelan, T. A. Sato, K. W. Marvin, J. Lander,
R. S. Gilmour, and M. D. Mitchell, “15-deoxy-Δ12,14-
prostaglandin J2 a ligand for peroxisome proliferator-
activated receptor-γ, induces apoptosis in JEG3 choriocarci-
noma cells,” Biochemical and Biophysical Research Communi-
cations, vol. 262, no. 3, pp. 579–585, 1999.
[176] D.-H. Nam, S. Ramachandran, D.-K. Song, et al., “Growth
inhibition and apoptosis induced in human leiomyoma cells
by treatment with the PPAR γ ligand ciglitizone,” Molecular
Human Reproduction, vol. 13, no. 11, pp. 829–836, 2007.