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.
The Nurse Practitioner 3(4):31-2.
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ABSTRACT: Using a data set of women who longitudinally recorded menstrual and reproductive events, we examined menstrual cycle characteristics in relationship to early and late menarche, early and late menopause, and deferred parity, three variables epidemiologically related to breast cancer incidence. Women with late onset of menarche had longer and more variable cycles in the 10 years after menarche than did those with early onset. Women with late onset of menopause had longer and more variable cycles in the premenopausal interval than did those with early onset. Cumulative fertility in women after marriage did not differ according to cycle length and variance. Late menopause may be a breast cancer risk factor due to relative estrogen excess and progesterone lack as reflected in longer, more varied cycle patterns. Observed cycle differences between women with early and late menarche await further study of the endocrine physiology of the menstrual cycle in those groups.Cancer Research 12/1978; 38(11 Pt 2):4021-4. · 7.86 Impact Factor
Article: Invasion and metastasis.[show abstract] [hide abstract]
ABSTRACT: Tumor metastasis remains a major cause of death for cancer patients. From a clinical perspective, treatment of metastatic disease remains difficult. The initial tumor cell invasive and locomotive events have been completed in many patients by the time of cancer diagnosis and surgery. This observation focuses attention on the last steps in the metastatic cascade for therapeutic development, ie, angiogenesis and colonization at the metastatic site. Emerging themes in metastasis research, including the molecular characterization of protease production and angiogenesis, the interrelationship of growth and metastasis, and the genetic control of the metastatic process are discussed.Current Opinion in Oncology 03/1992; 4(1):134-41. · 4.10 Impact Factor
Hindawi Publishing Corporation
Volume 2009, Article ID 345320, 13 pages
ObesityandBreast Cancer:TheRolesof Peroxisome
Proliferator-Activated Receptor-γ and Plasminogen
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, firstname.lastname@example.org
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
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
. 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 . Five-
year survival rates of breast cancer patients is almost 90%,
although higher in patients over 40, as women diagnosed at
mortality rates have decreased in recent years, the healthcare
costs and the emotional costs of breast cancer remain high.
of breast cancer. The greatest risk factors are age and
gender, with females developing breast cancer 100 times
more frequently than males . 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 .
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 . Surrounding these epithelial cells is a network
of fibroblasts, which generate the proteins of the breast
is adipose, composed of mesenchymal precursor cells and
the mature adipocytes . In addition to energy stores,
adipocytes synthesize and secrete a number of cytokines,
which are involved in a number of pathogenic processes,
including inflammation .
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,
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 overall goal of this paper is to present evidence
supporting the link between how a high-fat diet and obesity
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 . 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
. In terms of breast cancer, the most common sites of
metastases are bone, brain, and lung . In order to move
to distant sites, these cells must degrade the surrounding
extracellular matrix (ECM) and invade nearby blood and
lymph vessels . The plasminogen activator (PA) system
allows tumor cells to activate plasminogen, resulting in the
active proteolytic enzyme plasmin and ECM degradation
. In breast cancer, this system is often dysregulated,
resulting in migration and invasion of tumor cells into the
surrounding vasculature and lymphatics .
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
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 , 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–
3.The Plasminogen ActivatorSystemin
The role of the PA system is to regulate fibrinolysis and
to promote pericellular proteolysis . 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].
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 . 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
tumor cells could then invade into the surrounding blood
vessels and lymphatics, becoming metastases of the primary
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 .
Though the physiological activator is unknown, in vitro a
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 . 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
Urokinase receptor (uPAR)
Extracellular matrix (ECM)
Tumor cell invasion
Integrin binding site (RGD)
VN somatomedin B domain:
PAI-1 and uPAR binding site
Ternary complex (PAI-1/uPA/uPAR)
internalization and cell signaling
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 .
and plays a key role in uPA activation. Research has also
shown uPAR mediates cell proliferation through activation
Examination of uPAR protein levels in several breast cancer
cell lines showed a correlation with invasiveness in vitro
. In breast cancer patients, combined overexpression of
3.3. Plasminogen Activator Inhibitor Type-1. PAI-1 is a gly-
coprotein of approximately 50kDa  and a member of
the serine protease inhibitor (serpin) superfamily of proteins
. 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 . 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 , and increased migra-
tion . In addition to the role of PAI-1 in breast
cancer migration and invasion, it has been implicated in
an inflammatory response , neutrophil recruitment, and
in proliferation of smooth muscle cells . 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–
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 . 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
Besides their traditional role as energy stores, adipocytes
are now considered to be an important “endocrine gland”,
Table 1: Relationship between obesity, PPAR-γ, fatty acids, and increased risk of breast cancer
ComponentAssociation with obesity Association with breast cancer
Breast epithelial cells,
endothelial cells, smooth
muscle cells, adipocytes
[61, 72] [14, 73]
Tumor cells, epithelial
epithelial cells, tumor
Breast epithelium, 
[71, 80, 81]
Adipocytes [82, 83]
[6, 84][80, 85]
Adipocytes, tumor cells
[86, 87][88, 89]
[90, 91][92, 93]
[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 .
It is hypothesized this is a key reason for the increased
risk of developing breast cancer in obese postmenopausal
Another factor expressed in the adipose tissue is the
hormone leptin. In obese individuals, leptin is overex-
pressed . 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].
mediated breast cancer cell growth in vitro . Studies
have shown an antitumor effect of adiponectin in breast
cancer. Treating cells with adiponectin decreases cell motility
and induces apotosis . 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 . 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
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 , 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 . PPAR-γ binds to
the target gene at a PPAR response element (PPRE),
where it initiates transcription through the recruitment of
transcriptional machinery . 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 . 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
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 . Altered expression of
nuclear NF-κB has also been shown to prevent apopto-
sis . Other studies have shown NF-κB is involved
in mammary epithelial proliferation [121, 122], and also
chemoresistance in MCF-7 breast cancer cells . 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
preventing IR transcription . Insulin receptor signaling
has been implicated in a number of neoplastic processes
including proliferation, invasion, and cell survival .
Recently, elevated levels of insulin in newly diagnosed breast
cancer patients were shown to be related to an underlying
insulin resistance . These data, and the fact that insulin
resistance is associated with increased risk of breast cancer
 and poor patient prognosis , 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 , ovaries , prostate [22, 88], colon ,
and breast . While the in vivo role of PPAR-γ in these
tumor cells is unknown, in vitro data suggests PPAR-γ
activation can induce apoptosis  and promote terminal
differentiation of breast tumor cells . 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 . 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 .
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 . 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
cancer patients with refractory disease . 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 . 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 . 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 . 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
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 .
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 . Adult weight
gain has also been associated with an increased risk of breast
cancer, particularly in women not on hormone replacement
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)
inactivation of the tumor suppressor PTEN , while
another group has shown that AA directly activates PI3K and
upregulates numerous inflammatory genes . 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 . 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 . 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 .
One group showed a differential effect of ω-3 versus ω-6
fatty acids on PPAR-γ transcriptional activity , 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
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
Increased long-chain ω-6 fatty acids in adipose tissue of
the breast have been shown to correlate with development of
acids had increased apoptosis and decreased proliferation,
suggesting a protective role of ω-3 fatty acids in tumor
progression . In breast cancer cells, gene expression is
differentially regulated by ω-3 and ω-6 fatty acids . A
number of animal studies also suggest a protective role for
ω-3 fatty acids in breast cancer progression . Recently,
a study showed ω-3 fatty acids inhibits HER-2/neu-induced
breast cancer in transgenic mice, independent of PPAR-γ
activity . Horia and Watkins  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
tumor volumes . 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 . Adipocytes have
been shown to promote tumor growth by secretion and
processing of collagen IV, which activates AKT signaling
pathway in breast epithelial cells . 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 . 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 , 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 .
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 , while expression of PPAR-γ
expression of cell-cycle molecules . 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 . 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 . Suzuki et al.
show PPAR-γ immunoreactivity in breast carcinoma tissue
was associated with improved clinical outcome . While
these studies reveal the presence of PPAR-γ in tumor cells,
Breast tumor cell
Extravasation from primary
Promotion of angiogenesis
ω-6 and ω-3
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
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  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
breast cancer patients.
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
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