Glucose Metabolism in Breast Cancer and its Implication in Cancer Therapy

Abstract

It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP) and de novo fatty acid synthesis in the breast tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor cells can be due to the elevated level of glucose transporter (GLUT) proteins, such as the over-expression of GLUT1 and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1), es-trogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas. Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investi-gated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism.

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International Journal of Clinical Medicine, 2011, 2, 110-128
doi:10.4236/ijcm.2011.22022 Published Online May 2011 (http://www.SciRP.org/journal/ijcm)
Copyright © 2011 SciRes. IJCM
Glucose Metabolism in Breast Cancer and Its
Implication in Cancer Therapy
Ning Li1, Wen Tan1, Jing Li2, Ping Li3, Simon Lee1, Yitao Wang1, Yuewen Gong4

1Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; 2Department of Endocrinology, Dong-Zhi-Men
Hospital, Beijing University of Chinese Medicine, Beijing, China; 3Department of Pharmacology, Institute of Clinical Medical Sci-
ence, China-Japan Friendship Hospital, Beijing, China; 4Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Email: ygong@cc.umanitoba.ca, ytwang@umac.mo

Received February 25th, 2011; revised March 8th, 2011; accepted March 22nd, 2011.

ABSTRACT
It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast
proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated
regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to
glycolysis and other pathways such as pentose phosphate pathway (PPP) and de novo fatty acid synthesis in the breast
tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor
cells can be due to the elevated level of glucose transporter (GLUT) proteins, such as the over-expression of GLUT1
and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1), es-
trogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas.
Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investi-
gated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment
that targets glucose metabolism.

Keywords: Breast Cancer, Glucose Transport, Glycolysis, Fatty Acid Synthesis, Mitochondrial Metabolism
1. Introduction
Rapid growth and cellular proliferation are hallmarks of
tumor. In order to survive, tumor cells have to adopt all
possible mechanisms to meet their energy needs. The in-
creased demand for energy also requires a higher me-
tabolic rate of nutrients. In non-malignant cells, this is usu-
ally achieved through elevating mitochondrial oxidative
phosphorylation (OXPHOS), which is the major source of
cellular ATP. By contrast, in cancer cells, observations
by Otto Warburg suggested that tumor cells might utilize
the augmented glycolysis rather than mitochondrial pho-
sphorylation of glucose as their main energy supply, and
apply this less efficient pathway even under aerobic con-
ditions [1]. This metabolic alternative is also closely as-
sociated with the aggressiveness of the tumor [2]. The
universal ‘aerobic glycolysis’ of tumors suggests a ‘meta-
bolic reprogramming’ of nutrients in those cells, which is
characterized by facilitated glycolytic reactions, impaired
OXPHOS and elevated de novo nucleotide and fatty acid
biosynthesis. Since the capability of tumor cells to sup-
port their enhanced nutrient metabolism is obligatory for
their growth and phenotype, mechanisms contributing to
these changes may provide a biochemical basis for the-
rapeutic strategies.
2. Glucose Metabolism in Cancer
Cells are highly organized and a constant supply of en-
ergy is required to create and maintain the biological
orders that keep them alive. This energy is derived from
the chemical bond stored in food molecules, which ser-
ves as fuel for cells. Glucose is a particularly important
fuel molecule and dominates energy production in most
animal cells. Generally, glucose metabolism provides che-
mical energy in the form of ATP and NADH through con-
trol of three-step continuous reactions, including gly-
colysis, the tricarboxylic acid (TCA) cycle and OXPHOS.
The breakdown of each molecule of glucose into two
smaller molecules of pyruvate is carried out through ‘gly-
colysis’, which involves a sequence of ten separate reac-
tions, each of which produces different intermediates and
is catalyzed by different enzymes. During glycolysis,
energy is produced as activated carrier molecules (ATP
and NADH) and at the end of glycolysis, there is a net

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Glucose Metabolism in Breast Cancer and Its Implication in Cancer Therapy
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gain of two molecules of ATP for each glucose molecule
that is metabolized. For many anaerobic organisms, gly-
colysis is the principal source of cellular ATP. By con-
trast, in most aerobic tissues, the pyruvate derived from
glycolysis directly enters mitochondria, in which each
molecule of pyruvate is converted to acetyl-CoA and CO2.
The complete oxidation of the acetyl groups in ace-
tyl-CoA to CO2 occurs in the TCA cycle, starting from
citrate formation by the joining of acetyl-CoA to ox-
aloacetate (OAA). Moreover, this cycle accounts for two-
thirds of total oxidation of carbon compounds in most
cells and generates high-energy electrons carried by
NADH and FADH2. These high-energy electrons are then
passed to an electron transport chain embedded in the
inner mitochondrial membrane, which eventually com-
bine with O2 to form H2O. With the movement of elec-
trons along the respiratory chain, energy from NADH
and FADH2 is stored as an electrochemical proton gra-
dient across the inner membrane of mitochondrial, which
exerts a proton-motive force, driving the conversion of
ADP and phosphate to ATP. Compared to glycolysis, mi-
tochondrial OXPHOS produces 36 molecules of ATP per
one molecule of glucose. Efficient OXPHOS relies on
functional enzyme complexes of the mitochondrial res-
piratory chain, which are encoded by both nuclear and
mitochondrial genes. Therefore, any deletions and muta-
tions of mitochondrial DNA (mtDNA) will result in a
defect of mtDNA-encoded polypeptides, which can cause
a large spectrum of diseases featuring impaired mito-
chondrial metabolism such as cancer.
Cancer cells, characterized by uncontrolled prolifera-
tion in the hypoxic and poorly vascularized environment,
require a significant amount of glucose and accelerated
glucose metabolism to meet their need for energy and bio-
synthetic elements. However, a metabolic alteration ob-
served by Otto Warburg (Warburg effect) in 1924, su-
ggested that in contrast to non-malignant cells, which
utilize mitochondrial OXPHOS to produce ATP in the
presence of adequate oxygen and anaerobic glycolysis
when adequate oxygen supply is not available, malignant
cells preferentially depend on converting glucose into
lactate rather than mitochondrial glucose metabolism even
under high oxygen environments [1]. Though the exact
molecular mechanisms underlying the ‘Warburg effect’
are unknown, the ‘aerobic glycolysis’, which presents ele-
vated glucose transport, increased glycolytic activity and
reduced mitochondrial glucose metabolism, has been one
of the important tumor metabolic phenotypes. The ad-
vantage of this shifted energy conversion is likely to pro-
vide tumor cells adequate microenvironment for multiple
bioenergetic and biosynthetic pathways [3].
2.1. Facilitated Glycolysis
Glycolytic enzymes in malignant cells were distinctive
from their counterparts in normal cells [4-6]. For instance,
phosphoglycerate mutase (PGM) and enolase, catalyzing
glucose to pyruvate—the end-product of glycolysis, were
phosphorylated at the tyrosine residues in the cells trans-
formed with Rous sarcoma virus or stimulated by growth
factors [7]. The same was observed with lactate dehy-
drogenase (LDH)-A, which is responsible for the conver-
sion of pyruvate to lactate—a main product of anaerobic
pathway. The phosphorylation level of these three en-
zymes correlated with the increased rate of glycolysis [7].
Typically in malignant human breast tissue, the over-
expression of LDH-A was associated with tumor inva-
siveness. Accordingly, LDH-A has been proposed as a
marker of tumor progression [8].
In addition to the phosphorylation of glycolytic en-
zymes, the enzyme activities were significantly increased
in the malignant breast tissues compared to the normal
and benign breast tissues, such as hexokinase (HK), pho-
sphofructokinase (PFK), aldolase and pyruvate kinase (PK)
(see Glycolysis in the Figure 1) [5,9]. For example, HK
activation was related to the suppression of apoptosis since
the promoter region of the HK gene contains the DNA
responsible elements of both p53 and hypoxia-inducible
factor (HIF)-1, and both mutated p53 and HIF-1 in-
creased the HK expression [10]. HIF-1 is considered as
an oxygen sensor and is stabilized under hypoxic stress.
It transcriptionally modulates a number of genes as a
metabolic adaptation in cancer cells [11,12]. HIF-1-in-
duced activation of HK triggers the transloca-tion of HK
from the cytoplasm to mitochondrial membranes with
which it interacts and suppresses several key components
of mitochondria-dependent apoptotic proteins [13].
Moreover, the activity of PK, which irreversibly cata-
lyzes the last step of pyruvate formation, has been shown
to have a strong connection with the malignancy of
breast carcinomas [14].
The glycolytic end-product pyruvate is consumed dif-
ferently in tumors. Pyruvate metabolism stands at the
crossroad between oxidative and glycolytic pathways.
Transportation of pyruvate into mitochondria results in its
oxidation, whereas its maintenance in cytosol leads to the
reduction of pyruvate. The inhibition of pyruvate oxi-
dation in mitochondria is considered as a metabolic de-
viation that could explain Warburg effect of tumor cells
[15]: down-regulation of pyruvate oxidation by phospho-
rylated pyruvate dehydrogenase (PDH) complex would
redirect pyruvate into the cytoplasm, which will then be
metabolized into lactate. Moreover, the mitochondrial
metabolic flux of pyruvate through the lefthand side of
the TCA cycle (from α-ketoglutarate to OAA) is much
greater than that through the right-hand side (from ace-
tyl-CoA to α-ketoglutarate), which may be due to the
higher rate of glutaminolysis in tumor [16].
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Glucose Metabolism in Breast Cancer and Its Implication in Cancer Therapy
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Figure 1. A brief outline from glucose uptake to mitochondrial metabolism followed by de novo nucleotide and fatty acid bio-
synthesis involved in this review.

Glutaminolysis is the degradation of amino acid gluta-
mine to glutamate, pyruvate and then lactate. Therefore,
the consequence of accelerated glutaminolysis in tumor
cells is an increased conversion of pyruvate into lactate.
In supporting this information, several studies reported
that there were higher utilization of both glucose and
glutamine to generate lactate in tumor cells [17,18]. As
glutaminolysis is an energy producing pathway, the ap-
plication of glutaminolysis in tumor cells could be an
adaptive metabolic switch in order to satisfy the ATP re-
quirement [18]. Additionally, the reduced mitochondrial
pyruvate oxidation was accompanied by an increased
activity of cytosolic pyruvate enzymes in tumor cells,
which would reduce the amount of this substrate trans-
ported to and metabolized in the mitochondria [19, 20].
The key molecule that drives glycolysis in cancer cells
is HIF-1. HIF-1 is more stabilized in conditions such as
nutrient depletion and reduced oxygen or hypoxic condi-
tions. HIF-1 has been shown to induce the expression of
several glucose transporters as well as most enzymes re-
quired for glycolysis [21]. Besides increasing the expre-
ssion of HK in anaerobic metabolism, HIF-1 can also su-
ppress PDH in mitochondria by inducing pyruvate de-
hydrogenase kinase (PDK)-1, which inhibits PDH acti-
vity by phosphorylation [22,23]. Since PDH catalyzes the
mitochondrial oxidation of pyruvate to produce NADH
and acetyl-CoA for ATP production, the inhibition of
PDH by HIF-1 will result in a restricted entry of pyruvate
into the mitochondria, a decrease of oxygen consumption,
and consequently the transmission of metabolic flux to
the lactate pathway [24]. Moreover, in malignant cells,
there was a higher level of fructose-2, 6-bisphosphate
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Glucose Metabolism in Breast Cancer and Its Implication in Cancer Therapy
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(F-2, 6-BP), which is a powerful allosteric activator of
glycolytic enzyme PFK-1. This increase could be due to
a phosphorylative induction by the PFK-2 portion of the
bifunctional enzyme PFK-2/fructose-2, 6-bisphosphatase
in a HIF-1-dependent manner [25]. Furthermore, HIF-1
plays a transcriptional role in promoting LDH-A expres-
sion [26], which would attenuate tumor cell respiration
and viability [27].
Diverting metabolism away from mitochondria to-
wards cytoplasm provides malignant cells resistant to apo-
ptosis. When cells switch from OXPHOS towards higher
glycolysis, the consequent formation and accumulation of
lactate can lead to cellular acidification, which would
eventually facilitate tumor growth through acid-mediated
extracellular matrix degradation and favour tumor inva-
sion and metastasis (see Acidification in the Figure 1)
[28]. Consequently, the persistence of this adaptive me-
tabolic mechanism grants tumor cells a request of growth
advantages. In this context, glycolytic enzymes serve as
anti-apoptotic factors through inhibiting several compo-
nents of mitochondria-dependent apoptosis [9, 29]. Addi-
tionally, the genetic theory of carcinogenesis regards
glycolytic transformation as a consequence of activation
of various oncogenes or tumor suppressor genes, includ-
ing Akt/PTEN, p53 and c-myc [30]. Up-regulated Akt
can be found in many cancers and could induce a glyco-
lytic metabolic profile through augmenting HK expres-
sion and activity [31,32]. The PTEN (the antagonizer of
Akt) appears to be mutated in several cancers, which
fails to control the activity of Akt. Gene p53 can also
influence the metabolic balance in cells between glyco-
lysis and OXPHOS. The p53 activity can favour OX-
PHOS through a transcriptional regulation of F-2, 6-BP
by TIGAR (a p53-induced glycolysis and apoptosis re-
gulator). TIGAR negatively regulates glycolysis by de-
grading F-2, 6-BP, which activates glycolytic enzyme
PFK1 [33]. Moreover, p53 contributes to the synthesis of
cytochrome c oxidase (COX)—a subunit of mitochon-
drial electron transport chain complex IV [30,33,34].
Restoring impaired COX is able to promote the conver-
sion of ATP production from glycolysis to OX-PHOS
[34]. Accordingly, p53 mutation would result in the
switch of ATP production from OXPHOS to glycolysis.
Therefore, the metabolic phenotype is essential for the
pathogenesis of cancer but not a ‘by-product’ of car-
cinogenesis.
2.2. Altered Mitochondrial Machinery
The original Warburg hypothesis was that it could be the
damage of mitochondrial respiration that contributes to
the enhanced glycolysis in tumor cells [1]. Mitochondria
have been suggested to play an important role as an oxy-
gen sensor to initiate the HIF-1 pathway under hypoxia
[35]. Once hypoxia is initiated, reactive oxygen species
(ROS) will accumulate on the site of complex III Q0 of
mitochondrial respiratory chain and will stabilize rather
than degrade the regulatory subunit of HIF-1 [35,36].
This results in the augmentation of HIF-1-induced gene
expression and suppression of mitochondrial metabolism
[22,23]. The role of mitochondria-derived ROS has also
been implicated in a proposed vicious cycle linking
mtDNA mutation in tumors. On the one hand, a burst of
ROS production from mitochondria would favour oxida-
tive dependent mitochondrial mutagenesis and hence
promote tumorigenesis [37]; While on the other hand, mu-
tation of mtDNA in the respiratory chain components
could commence a cascade of events leading to an in-
crease in electron leakage and ROS over-generation in
the process of malignant transformation and tumor pro-
gression [38,39]. Several mtDNA mutations have been
found in breast tumors [40], and the presence of mtDNA
mutations in breast cancer cells is consistent with the
intrinsic susceptibility of mtDNA to damage and persis-
tent oxidative stress [41]. In terms of the oncogenesis of
mtDNA mutation, critical evaluation and interpretation
of the literature revealed that mtDNA mutation could
enhance the specificity of diagnosis, detection and pre-
diction of breast cancer growth and/or patients’ outcomes.
Therefore, the mtDNA mutation may be used as a new
molecular bio-marker for breast cancer [42].
The suppressed OXPHOS may also be interpreted as a
transient adaptation in cancer cells, which disconnects
glycolysis from dysfunctional OXPHOS, leaving glyco-
lysis as the predominant ATP source, and then followed
by an OXPHOS remodeling according to the growth de-
mand of the cancer. The preference for glycolytic pro-
duction of ATP in tumor cells could be due to 1) glyco-
lysis generates ATP more rapidly although it is less effi-
cient in long term than OXPHOS [43]; and 2) part of the
carbon intermediates from glycolysis could be used for
various biosynthetic pathways to keep a constant tumor
growth [44]. However, deficiencies in mitochondrial res-
piratory chain components such as mtDNA impairment
cannot explain tumorgenesis for different kinds of tumors
because in some cases the over-expression of respiratory
complexes was observed [45].
2.3. Glycolysis and Mitochondrial TCA Cycle
Provide Precursors for Tumor Biosynthesis
The persistent shift of malignant cells from mitochon-
drial OXPHOS to glycolysis for ATP production impli-
cates that alternative pathways may be involved in main-
taining cell growth. Despite of the energy production of
glucose, catabolism also produces building blocks for
tumor cells to divide and proliferate. Glycolytic interme-
diates formed in central catabolic reaction pathways can
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Glucose Metabolism in Breast Cancer and Its Implication in Cancer Therapy
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be siphoned off by other enzymes that use them as bio-
synthetic precursors to produce amino acids, nucleotides
and lipids for cell needs. Thus, the supply of materials for
biosynthesis is another primary metabolic alteration asso-
ciated with proliferating tumor cells from the view of
glycolysis and TCA cycle [46]. The majority of macro-
molecules required for proliferation are generated de
novo from glucose, which is controlled through chemical
modification of these large molecules in response to
changes in the cellular immediate environment [47]. The
presence of different glucose metabolic pathways in the
cell requires a precise regulation. For long-term adapta-
tion, glucose metabolism in tumor cells requires a balance
between elimination of some particular reaction path-
ways and elevation of the others to meet the minimum
requirements. Hence, branching pathways of glycolysis
and mitochondrial TCA cycle in malignant cells are likely
to function as a distinctive way for their uncontrolled
growth. These are of particulate interest in understanding
of the pentose phosphate pathway (PPP, also known as
hexose monophosphate shunt) for de novo nucleotide
biosynthesis and the de novo fatty acid synthesis in can-
cer cells.
2.3.1. Pentose Phosphate Pathway
Carbon derived from glycolytic flux to the PPP can be
utilized to generate ribose-5-phosphate for de novo nu-
cleotide biosynthesis. The large cellular nucleotide pool
as well as the level and activity of different rate-limiting
enzymes involved nucleotide synthetic pathways are the
critical elements of maximal cell proliferative capacity.
Compared with normal cells, tumor cells display an al-
tered nucleotide metabolism, such as the larger nucleo-
tide pool, higher enzymatic activity in nucleotide ana-
bolic pathway as well as lower enzymatic activity in nu-
cleotide catabolic pathway [48]. Understanding of the
nucleotide biosynthesis in malignant cells offers possi-
bilities to design selective therapies for human cancer.
Besides the generation of ribose-5-phosphate from PPP
to support nucleic acid synthesis, the reduced nicotina-
mide adenine dinucleotide phosphate (NADPH) was
formed during PPP to provide reducing equivalents for
not only lipid synthesis but also detoxification of reactive
oxygen species [49]. Activities of enzymes involved in
this pathway such as glucose-6-phosphate dehydrogenase
and 6-phosphogluconate dehydrogenase have been re-
ported to be increased in malignant breast tissues [50] as
well as carcinomas and cancer cell lines from other ori-
gin [4,51,52].
The remaining pyruvate from aerobic glycolysis that is
not converted to lactate enters the mitochondria and is
then extruded from the TCA cycle at various steps for
biosynthetic pathways to satisfy the increased demand of
cell proliferation. Pyruvate could be converted to acetyl-
CoA, which will join with OAA to form citrate in the
presence of citrate synthase. After translocation of citrate
from mitochondria to cytosol, cleavage of citrate back to
acetyl-CoA provides the precursor for the synthesis of
fatty acid, which may function as essential building ma-
terials of cell plasma membrane for rapid cancer growth
(see PPP and De novo FA Synthesis in the Figure 1).
2.3.2. Fatty Acid Synthesis
De novo fatty acid synthesis involves the conversion of
glucose to pyruvate and then to acetyl-CoA, which will
work together with OAA to generate citrate. Besides glu-
cose metabolism, metabolites from glutaminolysis pro-
vide another carbon source to facilitate de novo fatty acid
synthesis. During glutaminolysis, glutamate is produced
through deamination of glutamine and can be converted
to α-ketoglutarate, which is then metabolized through
TCA cycle to generate citrate [53]. The citrate formed
from both glucose and glutamine metabolism in mito-
chondria will be transported into the cytosol and broken
down to acetyl-CoA and OAA by ATP citrate lyase (ACL).
The acetyl-CoA generated by ACL was then carboxylated
to malonyl-CoA by a rate-limiting enzyme acetyl-CoA
carboxylase (ACC). In addition, malic enzyme and the
PPP produce the reducing equivalence NADPH for a
preparation of fatty acid synthesis. Fatty acid synthase
(FAS) is the major enzyme of lipogenesis. With the pro-
vision of NADPH, FAS catalyzes the condensation of
acetyl-CoA and malonyl-CoA for the de novo synthesis
of 16-carbon saturated free fatty acid palmitate (see De
novo FA Synthesis in the Figure 1) [54].
Fatty acids are the source of membrane components
such as phospholipids and glycolipids. It also provides
precursors of critical signaling molecules for prolifera-
tion and differentiation [55]. Fatty acids are generally
acquired from diet and high level of fat in the Western
food has been implicated in the development of human
malignancies including carcinomas of colon, breast and
ovarian [56-60]. In fact, except for some organs such as
the liver, adipose tissue and lactating mammary gland,
other normal cells rarely utilize de novo lipid synthesis
pathway [61,62]; in contrast, the de novo fatty acid syn-
thesis was significantly elevated in malignant tumors as
reported by Medes et al. [63]. Consistently, the expres-
sion of enzyme FAS is highly up-regulated in a variety of
human malignancies, but FAS is hardly detected in nor-
mal tissues [54]. Through immunohistochemical and me-
tabolic studies, FAS over-expression has been detected in
cancer tissues, its surrounding non-cancer tissues and in
the blood of patients with cancer [64-71]. Evidence from
breast cancer, prostate cancer, ovarian cancer and thyroid
cancer studies suggested an associa- tion of FAS expres-
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