Biomarkers of the Metabolic Syndrome and Breast Cancer Prognosis.
ABSTRACT In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer.
- SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: The increase in breast cancer incidence over recent decades has been accompanied by an increase in the frequency of metabolic syndrome. Several studies suggest that breast cancer risk is associated with the components of metabolic syndrome (high serum glucose and triglycerides, low HDL-cholesterol, high blood pressure, and abdominal obesity), but no prospective study has investigated risk in relation to the presence of explicitly defined metabolic syndrome. We investigated associations between metabolic syndrome, its components, and breast cancer risk in a nested case-control study on postmenopausal women of the ORDET cohort. After a median follow-up of 13.5 years, 163 women developed breast cancer; metabolic syndrome was present in 29.8%. Four matched controls per case were selected by incidence density sampling, and rate ratios were estimated by conditional logistic regression. Metabolic syndrome (i.e. presence of three or more metabolic syndrome components) was significantly associated with breast cancer risk (rate ratio 1.58 [95% confidence interval 1.07-2.33]), with a significant risk increase for increasing number of components (P for trend 0.004). Among individual metabolic syndrome components, only low serum HDL-cholesterol and high triglycerides were significantly associated with increased risk. This prospective study indicates that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women. Although serum HDL-cholesterol and triglycerides had the strongest association with breast cancer, all components may contribute to increased risk by multiple interacting mechanisms. Prevention or reversal of metabolic syndrome by life-style changes may be effective in preventing breast cancer in postmenopausal women.Nutrition, metabolism, and cardiovascular diseases: NMCD 05/2009; 20(1):41-8. · 3.52 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The staggering array of nanotechnological products, found in our environment and those applicable in medicine, has stimulated a growing interest in examining their long-term impact on genetic and epigenetic processes. We examined here the epigenomic and genotoxic response to cadmium telluride quantum dots (QDs) in human breast carcinoma cells. QD treatment induced global hypoacetylation implying a global epigenomic response. The ubiquitous responder to genotoxic stress, p53, was activated by QD challenge resulting in translocation of p53, with subsequent upregulation of downstream targets Puma and Noxa. Consequential decrease in cell viability was in part prevented by the p53 inhibitor pifithrin-alpha, suggesting that p53 translocation contributes to QD-induced cytotoxicity. These findings suggest three levels of nanoparticle-induced cellular changes: non-genomic, genomic and epigenetic. Epigenetic changes may have long-term effects on gene expression programming long after the initial signal has been removed, and if these changes remain undetected, it could lead to long-term untoward effects in biological systems. These studies suggest that aside from genotoxic effects, nanoparticles could cause more subtle epigenetic changes which merit thorough examination of environmental nanoparticles and novel candidate nanomaterials for medical applications.Journal of Molecular Medicine 04/2008; 86(3):291-302. · 4.77 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The relationships among blood pressure, obesity, glucose tolerance, and serum insulin concentration were studied in 2873 Pima Indians aged 18-92 yr (mean 37 yr). Age- and sex-adjusted to the Pima population, the prevalence of hypertension (systolic blood pressure greater than or equal to 160 mmHg, diastolic blood pressure greater than or equal to 95 mmHg, or receiving drug treatment) was 7.1% for subjects with normal glucose tolerance compared with 13.0% for subjects with impaired glucose tolerance (IGT) and 19.8% for those with non-insulin-dependent diabetes mellitus (NIDDM) (P less than 0.001). The prevalence ratio of hypertension was 1.8 (95% confidence interval [CI] 1.2-2.5) for IGT and 2.6 (95% CI 2.0-3.2) for NIDDM compared with normal glucose tolerance, controlled for age, sex, and body mass index (BMI). In logistic regression analysis, hypertension was positively related to age, male sex, BMI, glucose tolerance, and fasting but not 2-h postload serum insulin concentration. Among subjects not taking antihypertensive drugs, however, neither fasting nor 2-h postload serum insulin was significantly related to hypertension. Furthermore, in 2033 subjects receiving neither antihypertensive nor antidiabetic drugs, blood pressure was not significantly correlated to fasting insulin concentration, and 2-h postload serum insulin was negatively correlated with diastolic blood pressure. In conclusion, insulin is not significantly related to blood pressure in Pima Indians not receiving antihypertensive drugs. Higher insulin concentrations in drug-treated hypertensive patients might result from the treatment rather than contribute to the pathogenesis of hypertension. Thus, these data do not support a major role for insulin in determining the occurrence of hypertension or regulation of blood pressure in Pima Indians.Diabetes 12/1990; 39(11):1430-5. · 7.90 Impact Factor
Cancers 2010, 2, 721-739; doi:10.3390/cancers2020721
Biomarkers of the Metabolic Syndrome and Breast Cancer
Qiu-Li Zhu 1, Wang-Hong Xu 1,* and Meng-Hua Tao 2,*
1 Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China
2 Department of Social and Preventive Medicine, School of Public Health and Health Professions,
University at Buffalo, Buffalo, NY 14214, USA
* Author to whom correspondence should be addressed; E-Mails: email@example.com (M.H.T.);
firstname.lastname@example.org (W.H.X.); Tel.: +1-716-829-5339.
Received: 23 March 2010; in revised form: 13 April 2010 / Accepted: 26 April 2010 /
Published: 28 April 2010
Abstract: In spite of its public health importance, our understanding of the mechanisms of
breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a
constellation of biochemical abnormalities including visceral adiposity, hyperglycemia,
hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all
been related to late-stage disease and even to a poor prognosis of breast cancer through
multiple interacting mechanisms. In this review, we aim to present a summary of recent
advances in the understanding of the contribution of the MS to breast cancer with the
emphasis on the role of biomarkers of the MS in the prognosis of breast cancer.
Keywords: metabolic syndrome; breast cancer; epidemiology; biomarkers; prognosis
Breast cancer is the most common cancer affecting women. Although many risk and prognostic
factors of breast cancer have been established, and numerous biomarkers have been linked to breast
cancer, our understanding of breast cancer prognosis is still evolving. In recent years, evidence has
rapidly accumulated on the potential role of multiple metabolic disorders in the development and
progress of breast cancer. The metabolic syndrome (MS), a cluster of metabolic disorders that are the
Cancers 2010, 2
known risk factor of cardiovascular disease and diabetes, has been proposed to play a critical role in
the risk  and prognosis of breast cancer .
There are several commonly used definitions of the MS [3–5], including a newly-developed
harmonized one . These definitions, although with slightly different emphasis, can be distilled into
the presence of at least three metabolic abnormalities among central obesity, dyslipidemia (high
triglycerides or low HDL-cholesterol levels), hyperglycemia and elevated blood pressure. The four
features have been demonstrated to be closely related to breast cancer risk [7–12], and some have been
identified to be associated with late-stage of the disease and a poor prognosis [13–16]. Meanwhile, the
effect of these metabolic disorders on breast cancer survival can be modified by multiple factors [16–19].
As the MS has experienced an abrupt increase in recent decades , simultaneously the number of
female breast cancer survivors continues to rise globally; identifying the modifiable biomarkers of the
MS and breast cancer and the possible mechanism is of particular interest. In this review, we report on
current understanding of the contributions of the MS to the prognosis of breast cancer with emphasis
on the role of the biomarkers of the four most important features. We also aim to present a summary of
possible underlying mechanisms and the possible approaches to improve the breast cancer prognosis
through controlling the MS.
2. Obesity and Breast Cancer Survival
Generally, obesity, estimated by body weight, body mass index (BMI), or waist-to-hip ratio (WHR),
is positively associated with breast cancer risk in postmenopausal women, while inversely related to
the risk in premenopausal women. The effect of obesity on the prognosis of both pre- and
post-menopausal breast cancer has aroused increasing interest in recent years, and has immense public
Body weight is a direct biomarker of obesity. Previous studies have found that heavier women
diagnosed with breast cancer are more likely to experience poorer survival and have an increased
likelihood of recurrence of the disease. Donegan et al.  first reported that, among 2,627 breast
cancer cases, recurrence rates were much higher among breast cancer patients who weighed more than
130 pounds compared to the leaner cases. Similar adverse effects of increased body weight on the
survival of breast cancer have been reported in the majority of later studies over the past three
decades [21–23]. A meta-analysis found that for increased body weight, the hazard ratios (HR) were
1.78 (95% CI, 1.50–2.11) and 1.36 (95% CI, 1.19–1.55) for recurrence risk after five years of breast
cancer diagnosis and death of the disease at 10 years, respectively . The negative effects of body
weight on breast cancer prognosis were observed in both pre- and post-menopausal
women [21–23,25,26], and some studies even reported stronger associations in premenopausal
women [25,26]. However, some of earlier studies did not find any association of body weight with
subsequent recurrence and/or survival [27,28]. These reported differences may be due to the relative
small sample sizes of some studies or alternatively if menopausal status and other confounding factors
such as body fat distribution were not taken into consideration [21,23,27]. Furthermore, most previous
studies only focused on the association of body weight measured at the time of diagnosis with breast
cancer prognosis, and overlooked the effects of weight changes after diagnosis and during the
treatment on recurrence and survival .
Cancers 2010, 2
BMI, measured as weight (kg)/height (m2), is another biomarker of obesity, and increasing BMI is
related to prognosis of breast cancer as shown in extensive reviews in recent years [22,29–33]. In an
early study by Greenberg et al. , BMI was not related to premenopausal breast cancer survival.
However, in a population-based follow-up study of 1,177 young breast cancer patients (<45 years),
women in the highest quartile of BMI were 2.5 times more likely to die from the disease within five
years of diagnosis compared with women in the lowest quartile . It was also found that these
heavier women tended to have larger tumor size, higher histological grade, and were more likely to
have markers of high cellular proliferation than the thinner women . Other studies reported similar
associations between BMI at the time of diagnosis and poor outcomes among premenopausal women
with breast cancer [26,35,36]. Most, but not all, studies have confirmed the association between BMI
and breast cancer recurrence and survival in postmenopausal women [28,31,33,37]. Different from the
previous studies, a recent large-scale cohort of older breast cancer survivors (≥65 years), the Study of
Osteoporotic Fractures, showed an age-dependent relationship between BMI and survival among
postmenopausal breast cancer . At age 65 and 70 years, women with higher BMI had an increased
risk of breast cancer mortality compared with women with a BMI of 22.6; whereas, there was a reverse
association between BMI and the outcome among women aged 80 and 85 years.With the growth of
aging population in the worldwide, management of breast cancer among the elderly has been a
significant public health problem, and further studies on elderly breast cancer survivors are needed.
Increasing BMI has also been associated with a poorer prognosis among women with early stageand
invasive primary breast cancer [39–41]. The breast cancer patients with no positive nodes and being in
the highest quartile of BMI (>29) had an increased risk of death from the disease than those in the
lowest quartile (HR = 2.5, 95% CI, 1.2–5.2) . Similar associations between obesity and poor breast
cancer prognosis also have been reported in Asian or African American populations [15,42–45].
Compared with white breast cancer patients, African-American patients are more likely to have a
worse prognosis, which may be at least partially related to the higher prevalence of obesity in
African-Americans [43,45]. The relationship between overweight/obesity and breast cancer survival
and recurrence has also been demonstrated in Asian populations, which have the lowest breast cancer
mortality rates internationally [15,42,44]. Tao et al.  found that BMI was associated with increased
risks of death, and the effect of obesity was stronger among post- than pre-menopausal Chinese
women. Recently, another cohort study in China reported that breast cancer patients with a BMI ≥ 30
at diagnosis had the HRs of total mortality of 1.55 (95% CI: 1.10–2.17) and relapse/disease-specific
mortality of 1.44 (95% CI: 1.02–2.03) compared with patients with normal BMI .
Weight gain after diagnosis, especially among breast cancer patients with systematic adjuvant
therapy (i.e., chemotherapy and tamoxifen use), has been frequently reported [22,46,47]. In a cohort of
5,014 women with early-stage breast cancer, approximately 26%, 37% and 33% of breast cancer
survivors gained ≥5% of their at-diagnosis body weight during the first 6, 18 and 36 months after
diagnosis, respectively, and more weight gain was observed among those who had a more advanced
disease stage, were younger, had lower BMI at diagnosis, were premenopausal, or received
chemotherapy or radiotherapy during the first six months after cancer diagnosis . In recent years,
some studies have investigated the effects of weight gain after breast cancer diagnosis on survival and
mortality in different populations [22,30]. It was reported that each 5-kg weight gain after breast
cancer diagnosis was associated with a 13% increase in breast cancer-specific mortality . In
Cancers 2010, 2
another study by Camoriano et al. , premenopausal breast cancer patients who gained more than
5.9 kg were 1.6times more likely to die from the disease than women who gained less. Chen et al. 
recently reported similar findings. Furthermore, results from the Nurses’ Health Study showed that the
association of weight gain after breast cancer diagnosis and increased breast cancer mortality was
limited among women who were of normal weight (BMI < 25) before diagnosis . Results from
these studies suggest that efforts to maintain or decrease body weight after a breast cancer diagnosis is
very important for breast cancer survivors, even for those who were overweight before diagnosis;
breast cancer patients, particularly those receiving adjuvant chemotherapy, may benefit from
maintaining or decreasing weight after breast cancer diagnosis through balancing energy intake (diet)
and consumption (physical activity) [49,50].
As a commonly used anthropometric indicator for abdominal obesity, WHR has been evaluated as a
critical biomarker for breast cancer survival by a number of studies in recent years [14,15,36,42,51]. In
a study of 603 breast cancer patients (357 postmenopausal), Borugian et al.  reported a strong
positive association between WHR and breast cancer mortality only in postmenopausal women.
Results from another large-scale cohort study showed that the highest quartile of WHR was associated
with increased mortality among young breast cancer cases aged 20–54 . Similar association
between high WHR and poor breast cancer survival was confirmed in a follow-up study . However,
the Iowa Women’s Health Study did not find any relationship between WHR before diagnosis and
survival of postmenopausal women with breast cancer . Results from two follow-up studies of
primary breast cancer patients in China showed no significant relationship between WHR or waist
circumference and breast cancer survival and mortality in Chinese women either [15,42]. The
differences between these observations may be partly due to the ethnic discrepancy in the body
composition profile across different populations. More studies are needed to evaluate the influence of
the abdominal obesity on the prognosis of breast cancer, while considering the potential impacts of the
use of hormone replacement therapy, breast tumor characteristics, and treatment after the disease diagnosis.
Several possible mechanisms have been hypothesized to account for the poorer prognosis of breast
cancer in obese women. Obesity usually makes the tumor harder to be detected at an early stage.
Consequently, obese women tend to be diagnosed at a more advanced stage, and thus have an
increased likelihood of treatments failing . Secondly, the higher endogenous levels of estrogen,
insulin and triglycerides in obese women may accelerate the growth and metastasis of the tumor. In
overweight/obese women, there may be enhanced conversion in the adipose tissue of the estrogen
precursor, androstenedione, to estrone, which can accelerate the tumor growth [54,55]. After
menopause, the adipose tissue predominately produces estrogen with concomitant increasing
concentration of triacylglycerol and insulin, which may result in prolonged exposure to increased and
more biologically active forms of estrogen in overweight postmenopausal women . Compared with
women with low WHR, women with high WHR have lower serum sex hormone binding globulin
(SHBG), higher free testosterone, and possibly higher estrogen levels [55,57]. The observed abdominal
obesity-survival association may be due to elevated concentrations of estrogen, as well as high levels
of insulin and triglycerides . Some studies have suggested that obesity is a marker for insulin
resistance and hyperinsulinemia [59,60], whose role in breast cancer survival will be discussed in the
next section. In addition, obesity is an index of positive energy balance characterized with excess fat
intake or lack of physical activity, which may act as an adverse contributor to poor prognosis of breast
Cancers 2010, 2
cancer [50,52]. Furthermore, obesity, particularly central obesity, could induce chronic low-grade
inflammation , which is another known risk factor of breast cancer and can increase the likelihood
of epigenetic alterations such as aberrant DNA methylation [62,63]. Aberrant DNA methylation plays a
crucial role in breast carcinogenesis [64,65], and shows promise as a potential biomarker in breast
cancer early detection and prognosis [66,67]. Breast cancer is heterogeneous; a better understanding of
the mechanisms and influences of epigenetic changes may lead to better treatment and improved
survival of certain subtypes of breast tumor.
Although the underlying mechanisms have not been completely understood [14,52], obesity is a
known factor of the poor prognosis of breast cancer. Because obesity can be modifiable through proper
diet and physical activity throughout the lifetime, weight management provides an important
opportunity to decrease mortality and improve quality of life for women with breast cancer.
3. Hyperinsulinaemia, Hyperglycemia and Type 2 Diabetes Mellitus with Breast Cancer Outcome
Insulin resistance, a central characteristic of the MS defined by WHO, is a state in which some
organs become resistant to the effect of insulin that is needed to shuttle glucose into cells. To
compensate for the resistance to insulin, the pancreas produces more insulin, which leads to an
increase in circulating levels of insulin. The compensation may continue for many years, but the
pancreas cannot maintain this high insulin output indefinitely, especially in some susceptible
individuals. The compensatory hyperinsulinaemia and the subsequent hyperglycemia due to insulin
resistance are believed to be the origin of the MS and type 2 diabetes mellitus and a crucial contributor
to breast cancer prognosis.
Hyperinsulinemia and hyperglycemia are biomarkers for insulin resistance . Both of these
disorders are critical to the initial development and progression of breast cancer. Berrino et al. 
found that, after adjusting for hormone receptor status and tumor stage at diagnosis, serum glucose was
significantly higher in patients who had a recurrence than those who did not in a prospective study.
More evidence is available for hyperinsulinemia. Goodwin et al.  firstly reported that in both
premenopausal and postmenopausal women, insulin levels were correlated with breast tumor stage,
nodal stage and tumor grade, and related to an increased risk of distance recurrence and a shorter
survival regardless of the BMI. Bozcuk et al.  found that the fasting serum insulin level was an
independent predictor for overall survival in metastatic breast cancer patients. Similar findings were
subsequently reported by Pasanisi et al.  and Pollak et al. , both of them observed a positive
association of high levels of insulin or C-peptide, a subunit of insulin, with breast cancer mortality.
Although whether hyperinsulinaemia and hyperglycemia increase the risk of breast cancer
recurrence and breast cancer specific mortality is not clear, multiple mechanisms through which the
conditions elicit adverse effects have been proposed. High circulating levels of glucose contribute to
the poor prognosis of breast cancer, possibly by providing abundant energy for proliferation of a
neoplastic cell, cultivating an amiable environment for the growth of malignant cell clones and
fostering cancer development . Moreover, concentration of glucose is mainly regulated by insulin,
a growth factor that can stimulate the growth of the tumors directly and indirectly . Insulin has an
important mitogenic effect and can signal growth directly through, at least in part, its own
receptors [75,76]. In cell culture, insulin induces a dose-dependent growth response in breast cancer
Cancers 2010, 2
cell lines acting via the insulin receptor [77,78], which has been demonstrated to be almost
ubiquitously present in human breast cancer and to have prognostic significance . The insulin
receptor has been related to tumor size , grade , and mortality of breast cancer .
Furthermore, insulin is highly regulated by endogenous sex hormones , particularly by estrogens -
the hormone involved in the promotion and growth of breast cancer . Hyperinsulinemia has
generally been related to an inhibition of aromatase activity , suppressed SHBG levels  and
thus elevated both free and combined available estrogen concentrations. More importantly, insulin can
interact and synergize with other growth promoting changes such as the insulin growth factor (IGF)
Hyperinsulinaemia could specifically augment IGF-1 levels and make cells more sensitive to the
growth factor. IGF-I is a small peptide (7,500 Da) with significant structural homology with proinsulin
and insulin . It is the main growth factor that inhibits apoptosis and stimulates cell proliferation
after puberty . IGF-1 has the nature to stimulate multiple cellular responses that are related to
growth such as synthesis of DNA, RNA, and cellular proteins  and induceing metastasis in many
types of malignancies . The IGF signaling system also interplays with estrogen activity on many
levels in the development and progression of breast cancer [90–92]. Moreover, it is possible that the
IGF system elicits adverse effects in the prognosis of breast cancer by inducing anti-cancer drug
resistance  and up-regulating expression of several genes that are involved in transport and
biosynthesis of amino acids . High circulating levels of IGF-I has been linked to poorer prognosis
of breast cancer [95–97], although the evidence is inconsistent [98–100]. IGF receptor I expression in
primary breast cancer has also been suggested as an independent favorable prognostic factor, while
IGF binding protein-3 (IGFBP-3) expression is associated with a poor outcome of breast cancer .
Recently, IGFBP-2 has been shown as another independent and positive predictor of overall survival of
breast cancer .
Insulin resistance and hyperinsulinaemia are also involved in prognosis of breast cancer by inducing
several other changes, such as increased inflammation  and elevated adipocytokines, which have
been related to angiogenesis . Therefore, hyperinsulinaemia may be most beneficially viewed as
one strand in a network of interacting disturbances that promote the development and progression
In recent years, type 2 diabetes mellitus, a complex disease characterized by hyperglycemia,
hyperinsulinemia, insulin resistance, obesity and other metabolic abnormalities, has been related to
breast cancer prognosis. Diabetic patients have experienced higher mortality and recurrence rates after
diagnosis and treatment for breast cancer. By analyzing the data from the Surveillance Epidemiology
and End Results (SEER) cancer registry, Yancik et al.  found that breast cancer patients with
diabetes were more likely to die prematurely from breast cancer than were patients without diabetes
(RR = 1.76; 95% CI: 1.23, 2.52). Verlato et al.  observed a higher risk of death from breast cancer
in diabetic women than among the general population (HR = 1.40; 95% CI: 1.06, 1.81) in a cohort of
3,782 diabetic women in northern Italy. Wolf and colleagues  reported that diabetic patients
present with breast cancer had adverse characteristics such as more advanced stage, larger tumor and
negative status of hormone receptors. The association could not be attributed to parity, family history
of breast cancer, and was independent of obesity, indicating that diabetes may have an independent
effect on cancer prognosis. A meta-analysis of five cohort studies on diabetes and mortality from breast
Cancers 2010, 2
cancer yielded a summary RR of 1.24 (95% CI, 0.95–1.62) for women with diabetes versus those
without, although only three out of five observed a significant association . In the largest study
with 588,321 subjects, RR of breast cancer mortality for diabetic women was 1.27 (95% CI, 1.11–1.45)
compared with the non-diabetic females after adjusting for age, race, BMI, physical activity, smoking,
and alcohol . A more recent retrospective cohort study linked diabetes with a close to 40%
increase in mortality within the first five-year following breast cancer . In this study, however, the
cause of death was not recorded and diabetic women without breast cancer also had an increase in
mortality, suggesting that diabetes rather than breast cancer was the major contributor to the increase in
mortality. Another meta-analysis also observed an increased mortality HR of 1.61(95% CI, 1.46–1.78)
for breast cancer with pre-existing diabetes mellitus . More recently, Patterson et al. 
observed over two-fold increased risk of additional breast cancer mortality in participants with a
history of early stage breast cancer and diabetes (HR = 2.5, 95% CI: 1.4, 4.4). Tseng et al. 
observed a 37–43% increase in breast cancer mortality in diabetic women in all age groups by
comparing the secular trend for breast cancer mortality rates in the general population and in diabetic
women in Taiwan.
Interestingly, evidence from an intensive care study indicates that achieving glucose control may
lead to better clinical outcomes of breast cancer . An animal study showed that insulin sensitizing
treatment is sufficient to abrogate type 2 diabetes-mediated mammary tumor progression . The
finding implicates a promising role of early administration of insulin-sensitizing therapy in prolonging
survival of breast cancer patients with type 2 diabetes mellitus. Goodwin and colleagues  have
administered Metformin, an oral anti-diabetic drug, to lower insulin levels in women with early breast
cancer, and are trying to evaluate the effect of the novel approach on breast cancer outcomes in the
later stage of the clinical trial.
As mentioned above, several mechanisms have been put forth for the adverse effect of
hyperinsulinaemia in the progression of breast cancer. However, it remains unclear whether diabetes
can make the cancer grow more aggressively or promote the sensitivity of the host organism to cancer
progression through these mechanisms. Currently, the comorbidity and interaction of diabetes with
breast cancer is arousing great research interest. It is supposed that the presence of diabetes may affect
the therapy of the breast cancer. While anti-diabetic drugs have a minor influence on cancer risk ,
drugs used to treat cancer may either worsen pre-existing diabetes  or increase
chemotherapy-related toxicities . Therefore, it is possible that diabetic patients have to receive
lower chemotherapy doses because the clinicians may consider the cardiac, renal, and neurologic
complications commonly associated with diabetes when they treat breast cancer. Ultimately, the
outcome for cancers may be worsened by the avoidance of agents that have been shown to provide the
best clinical response and survival in cancer patients without these disease complications. It has been
shown that diabetic cancer patients were frequently treated less aggressively and had a worse
prognosis compared to those without diabetes in a large population based analysis . It is also
possible that diabetic patients may have a worse response to chemotherapy compared with
non-diabetic individuals .
In conclusion, chronic hyperinsulinemia, either with or without clinically manifest type 2 diabetes
mellitus, is a possible factor favoring cancer progression due to the mitogenic effect of insulin. It needs
to be stressed, however, that no published studies have related type 2 diabetes mellitus,
Cancers 2010, 2
hyperinsulinemia, or insulin resistance specifically to breast cancer outcome. The complex and
multifactor-driven role of hyperinsulinemia in breast cancer prognosis has warranted further studies
including clinical trials to understand the nature of their relationship, particularly as the general
population ages and the magnitude of both health problems continues to grow.
4. Dyslipidaemia and Prognosis of Breast Cancer
Dyslipidaemia refers to an elevation in the concentrations of total cholesterol, the low-density
lipoprotein cholesterol (LDL-C) and the triglyceride (TG) concentrations, and a reduction in the
high-density lipoprotein cholesterol (HDL-C) in the blood. It often coexists with high levels of serum
insulin and obesity . As two important components of the MS , higher TG and lower HDL-C
levels in serum were found to be more common in patients with malignant diseases including breast
cancer compared with non-cancer subjects [121,122]. Some earlier studies have reported the
prognostic effect of serum cholesterol on the survival of breast cancer . Later, results from a study
by Vatten et al.  showed that breast cancer patients in the highest quartile of the preclinical total
serum cholesterol had an increased risk of dying from the disease compared to women in the lowest
quartile (HR = 2.0, 95% CI, 1.1–3.). A large scale prospective study, however, did not find significant
correlation between serum cholesterol level and breast cancer survival among both younger (aged < 50
years) and older (aged ≥ 60 years) patients . In a recent cohort study of 520 early-stage breast
cancer patients, after adjusting for age, tumor-related variables and BMI, a trend towards increased risk
of recurrence with higher total cholesterol was observed, although no significant associations between
fasting TG and breast cancer recurrence or death was found . These findings suggest that the
different fractions of cholesterol may contribute different influences to the relation between
dyslipidaemia and breast cancer prognosis.
Previous studies found that the turnover of TG was faster in breast cancer tissue than in the adjacent
normal tissue, indicating a significant difference in TG metabolism between the mammary
tissues [126,127]. Some studies also reported that women with relative androgen excess (such as
polycystic ovary syndrome) have lower levels of serum HDL-C, a suggested marker of androgen
status , compared with those having normal ovarian function . Low HDL-C is further related
to increased levels of several other hormones including estrogens, insulin, and IGF-I, all of which can
stimulate cancer development . The positive association between low HDL-C and breast cancer
risk may reflect the relative importance and mutual dependence of different pathways in the
progression of breast cancer, particularly among postmenopausal women. For postmenopausal women,
bio-available estrogens, the major stimulus for breast carcinogenesis, are mainly formed in fat tissue or
in the granulosa cells of the ovarian follicle through the aromatization of androstenedione and
testosterone instead of direct ovarian estrogen production . On the other hand, higher TG and
lower HDL-C levels have been constantly found to be correlated with insulin resistance and type 2
diabetes mellitus [132,133], and thus adversely affect the prognosis of breast cancer. Despite these
possible explanations, the mechanisms by which dyslipidemia affects survival of breast cancer are still
not well known, and further studies are needed.
Cancers 2010, 2
5. Hypertension and Prognosis of Breast Cancer
While a large amount of studies have evaluated the effects of obesity, hyperglycemia and
dyslipidemia on the prognosis of breast cancer, evidence for the influence of hypertension is still very
limited. So far, the association between hypertension and breast cancer survival has been investigated
in a few studies with inconsistent results. Results from a prospective study by a 19-year follow-up of
11,075 women showed that women who had hypertension at baseline had slightly increased total
mortality from cancer (HR = 1.10, 95% CI, 0.93–1.31); however, no association with breast cancer
mortality was observed . A recent study found that the prevalence of hypertension was much
higher in African-American breast cancer patients (63.4%) than that in white patients (35.5%), and the
presence of hypertension before breast cancer diagnosis was associated with worse survival,
particularly in African-American women . Recently, Braithwite et al.  evaluated the effect of
hypertension as an important comorbidity on breast cancer survival in 416 African-American and 838
white women. The presence of hypertension before breast cancer diagnosis was independently related
to all cause survival with the HR of 1.33 (95% CI, 1.07–1.67), and it accounted for 30% survival
disparity between African-American and white women diagnosed with breast cancer. Results from the
above two studies suggested that control of hypertension comorbidity may help to improve the overall
survival of African-American breast cancer patients and reduce racial disparity.
Results from both animal models [137,138] and human studies  have implicated that
hypertension may increase the response to carcinogens and initiate the process of carcinogenesis. The
potential mechanisms for the adverse impact of hypertension on the survival of breast cancer, however,
are much less clear. Insulin resistance may explain part of the possible association, because insulin
and/or insulin resistance are hypothesized to be associated with hypertension  by contributing to
the pathogenesis of the disorder . However, the evidence was also controversial, with a
strong [140,142] and null association between hypertension and insulin . More evidence is
needed to elucidate and to clearly understand the association between hypertension and breast
As described previously, the biomarkers for each individual component of the MS have been
indicated to be associated with breast cancer survival. It is plausible that the MS, a cluster of these
metabolic disorders, is associated with important clinical features of breast cancer and may act as a
predictor for breast cancer prognosis. Recently, Healy et al.  reported that the MS was associated
with more aggressive postmenopausal breast tumor biology. Patients with a later pathological stage
(II-IV) were significantly more likely to be obese, centrally obese, hyperglycaemic and
hyperinsulinaemic. As a result, the prevalence of the MS was higher (51%) in advanced stage disease
than in early stage disease (12%). Patients with node-positive disease were also significantly more
likely to be hyperinsulaemic and have the MS than patients with node-negative disease. Till now,
however, there are still few studies to examine the relationship of breast cancer survivorship with the
MS as a group of abnormal symptoms. After follow-up 110 postmenopausal breast cancer patients for
Cancers 2010, 2
5.5 years, Pasanisi et al.  found that the HR of subsequent recurrence of breast cancer was 3.0 (95%
CI, 1.2–7.1) for those diagnosed with the MS at baseline.
In conclusion, the MS may play an important role in the prognosis of breast cancer mediated by
insulin resistance, a state that is highly regulated by sex-hormone pathway and can stimulate growth of
malignant cells directly and indirectly through IGF signal pathway . Since both breast cancer and
the MS are of polygenic and multi-factorial origin and usually in comorbidity, their relationship is
definitely complex. If the role of the biomarkers of the MS in breast cancer survival is confirmed, it
may have an important implication in predicting and improving survival of breast cancer. The MS and
individual metabolic disorder can be prevented and modified by adopting healthy lifestyles; therefore,
it is possible to improve breast cancer prognosis through taking balanced diet, increasing physical
activities, controlling body weight [145–147], and potentially by administrating early insulin reducing
therapy [145–147]. There is a compelling need to carry out more long-term prospective studies and
large scale intervention trials with better design to evaluate both the short- and long-term effects of the
MS on breast cancer outcomes, to elucidate the preventive value of changes in lifestyle, and to better
understand the potential mechanisms.
Agnoli, C.; Berrino, F.; Abagnato, C.A.; Muti, P.; Panico, S.; Crosignani, P.; Krogh, V.
Metabolic syndrome and postmenopausal breast cancer in the ORDET cohort: a nested
case-control study. Nutr. Metab. Cardiovasc. Dis. 2010, 20, 41–48.
Pasanisi, P.; Berrino, F.; De Petris, M.; Venturelli, E.; Mastroianni, A.; Panico, S. Metabolic
syndrome as a prognostic factor for breast cancer recurrences. Int. J. Cancer. 2006, 119,
Alberti, K.G.; Zimmet, P.Z. Definition, diagnosis and classification of diabetes mellitus and its
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a
WHO consultation. Diabet. Med. 1998, 15, 539–553.
Denke, M. A.; Pasternak, R.C. Defining and Treating the Metabolic Syndrome: A Primer from
the Adult Treatment Panel III. Curr. Treat. Options. Cardiovasc. Med. 2001, 3, 251–253.
Alberti, K. G.; Zimmet, P.; Shaw, J. The metabolic syndrome--a new worldwide definition.
Lancet 2005, 366, 1059–1062.
Alberti, K.G.; Eckel, R.H.; Grundy, S.M.; Zimmet, P.Z.; Cleeman, J.I.; Donato, K.A.; Fruchart,
J.C.; James, W.P.; Loria, C.M.; Smith, S.J. Harmonizing the metabolic syndrome: a joint interim
statement of the International Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International Association for the Study of Obesity.
Circulation 2009, 120, 1640–1645.
Furberg, A.S.; Veierod, M.B.; Wilsgaard, T.; Bernstein, L.; Thune, I. Serum high-density
lipoprotein cholesterol, metabolic profile, and breast cancer risk. J. Natl. Cancer Inst. 2004, 96,
Morimoto, L.M.; White, E.; Chen, Z.; Chlebowski, R.T.; Hays, J.; Kuller, L.; Lopez, A.M.;
Manson, J.; Margolis, K.L.; Muti, P.C.; et al. Obesity, body size, and risk of postmenopausal
Cancers 2010, 2
breast cancer: the Women's Health Initiative (United States). Cancer Causes Contr. 2002, 13,
Folsom, A.R.; Kaye, S.A.; Prineas, R.J.; Potter, J.D.; Gapstur, S.M.; Wallace, R.B. Increased
incidence of carcinoma of the breast associated with abdominal adiposity in postmenopausal
women. Am. J. Epidemiol. 1990, 131, 794–803.
10. Peeters, P.H.; van Noord, P.A.; Hoes, A.W.; Fracheboud, J.; Gimbrere, C.H.; Grobbee, D.E.
Hypertension and breast cancer risk in a 19-year follow-up study (the DOM cohort). Diagnostic
investigation into mammarian cancer. J. Hypertens. 2000, 18, 249–254.
11. Muti, P.; Quattrin, T.; Grant, B. J.; Krogh, V.; Micheli, A.; Schunemann, H.J.; Ram, M.;
Freudenheim, J.L.; Sieri, S.; Trevisan, M.; Berrino, F. Fasting glucose is a risk factor for breast
cancer: a prospective study. Cancer Epidemiol. Biomarkers Prev. 2002, 11, 1361–1368.
12. Lipscombe, L.L.; Goodwin, P.J.; Zinman, B.; McLaughlin, J.R.; Hux, J.E. Diabetes mellitus and
breast cancer: a retrospective population-based cohort study. Breast Cancer Res. Treat. 2006, 98,
13. Donegan, W.L.; Hartz, A.J.; Rimm, A.A. The association of body weight with recurrent cancer of
the breast. Cancer 1978, 41, 1590–1594.
14. Borugian, M.J.; Sheps, S.B.; Kim-Sing, C.; Olivotto, I.A.; Van Patten, C.; Dunn, B.P.; Coldman,
A.J.; Potter, J.D.; Gallagher, R.P.; Hislop, T.G. Waist-to-hip ratio and breast cancer mortality. Am.
J. Epidemiol. 2003, 158, 963–968.
15. Tao, M.H.; Shu, X.O.; Ruan, Z.X.; Gao, Y.T.; Zheng, W. Association of overweight with breast
cancer survival. Am. J. Epidemiol. 2006, 163, 101–107.
16. Lipscombe, L.L.; Goodwin, P.J.; Zinman, B.; McLaughlin, J.R.; Hux, J.E. The impact of diabetes
on survival following breast cancer. Breast Cancer Res. Treat. 2008, 109, 389–395.
17. Irwin, M.L.; McTiernan, A.; Bernstein, L.; Gilliland, F.D.; Baumgartner, R.; Baumgartner, K.;
Ballard-Barbash, R. Relationship of obesity and physical activity with C-peptide, leptin, and
insulin-like growth factors in breast cancer survivors. Cancer Epidemiol. Biomarkers Prev. 2005,
18. Peeters, P.H.; van Noord, P.A.; Hoes, A.W.; Grobbee, D.E. Hypertension, antihypertensive drugs,
and mortality from cancer among women. J. Hypertens. 1998, 16, 941–947.
19. Josefson, D. High insulin levels linked to deaths from breast cancer. BMJ 2000, 320, 1496.
20. Procopiou, M.; Philippe, J. The metabolic syndrome and type 2 diabetes: epidemiological figures
and country specificities. Cerebrovasc. Dis. 2005, 20 (Suppl. 1), 2–8.
21. Tartter, P.I.; Papatestas, A.E.; Ioannovich, J.; Mulvihill, M.N.; Lesnick, G.; Aufses, A.H., Jr.
Cholesterol and obesity as prognostic factors in breast cancer. Cancer 1981, 47, 2222–2227.
22. Chlebowski, R.T.; Aiello, E.; McTiernan, A. Weight loss in breast cancer patient management.
J. Clin. Oncol. 2002, 20, 1128–1143.
23. Boyd, N.F.; Campbell, J.E.; Germanson, T.; Thomson, D.B.; Sutherland, D.J.; Meakin, J.W.
Body weight and prognosis in breast cancer. J. Natl. Cancer Inst. 1981, 67, 785–789.
24. Goodwin P.J.; Esplen M.J.; Winocur J.; Butler K.; Pritchard K.I. Development of a Weight
Management Program in Women with Newly Diagnosed Locoregional Breast Cancer; Bitzer J.,
Stauber M., Eds.; Psychosomatic Obstetrics and Gynecology: Bologna, Italy, 1995; pp. 491–496.
Cancers 2010, 2
25. Greenberg, E.R.; Vessey, M.P.; McPherson, K.; Doll, R.; Yeates, D. Body size and survival in
premenopausal breast cancer. Br. J. Cancer 1985, 51, 691–697.
26. Kroenke, C.H.; Chen, W.Y.; Rosner, B.; Holmes, M.D. Weight, weight gain, and survival after
breast cancer diagnosis. J. Clin. Oncol. 2005, 23, 1370–1378.
27. Obermair, A.; Kurz, C.; Hanzal, E.; Bancher-Todesca, D.; Thoma, M.; Bodisch, A.; Kubista, E.;
Kyral, E.; Kaider, A.; Sevelda, P.; et al. The influence of obesity on the disease-free survival in
primary breast cancer. Anticancer Res. 1995, 15, 2265–2269.
28. Healy, L.A.; Ryan, A.M.; Rowley, S.; Boyle, T.; Connolly, E.; Kennedy, M.J.; Reynolds, J.V.
Obesity increases the risk of postmenopausal breast cancer and is associated with more advanced
stage at presentation but no impact on survival. Breast J. 2010, 16, 95–97.
29. Carmichael, A.R. Obesity as a risk factor for development and poor prognosis of breast cancer.
BJOG 2006, 113, 1160–1166.
30. Carmichael, A.R. Obesity and prognosis of breast cancer. Obes. Rev. 2006, 7, 333–340.
31. Carmichael, A.R.; Bates, T. Obesity and breast cancer: a review of the literature. Breast 2004, 13,
32. Barnett, J.B. The relationship between obesity and breast cancer risk and mortality. Nutr. Rev.
2003, 61, 73–76.
33. Goodwin, P.J.; Boyd, N.F. Body size and breast cancer prognosis: a critical review of the
evidence. Breast Cancer Res. Treat. 1990, 16, 205–214.
34. Daling, J.R.; Malone, K.E.; Doody, D.R.; Johnson, L.G.; Gralow, J.R.; Porter, P.L. Relation of
body mass index to tumor markers and survival among young women with invasive ductal breast
carcinoma. Cancer 2001, 92, 720–729.
35. Loi, S.; Milne, R. L.; Friedlander, M. L.; McCredie, M. R.; Giles, G. G.; Hopper, J. L.; Phillips,
K. A. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer
Epidemiol. Biomarkers Prev. 2005, 14, 1686–1691.
36. Abrahamson, P.E.; Gammon, M.D.; Lund, M.J.; Flagg, E. W.; Porter, P. L.; Stevens, J.; Swanson,
C.A.; Brinton, L.A.; Eley, J.W.; Coates, R.J. General and abdominal obesity and survival among
young women with breast cancer. Cancer Epidemiol. Biomarkers Prev. 2006, 15, 1871–1877.
37. Rosenberg, L.; Czene, K.; Hall, P. Obesity and poor breast cancer prognosis: an illusion because
of hormone replacement therapy? Br. J. Cancer 2009, 100, 1486–1491.
38. Reeves, K.W.; Faulkner, K.; Modugno, F.; Hillier, T.A.; Bauer, D.C.; Ensrud, K.E.; Cauley, J.A.
Body mass index and mortality among older breast cancer survivors in the Study of Osteoporotic
Fractures. Cancer Epidemiol. Biomarkers Prev. 2007, 16, 1468–1473.
39. Newman, S.C.; Lees, A.W.; Jenkins, H.J. The effect of body mass index and oestrogen receptor
level on survival of breast cancer patients. Int. J. Epidemiol. 1997, 26, 484–490.
40. Tretli, S.; Haldorsen, T.; Ottestad, L. The effect of pre-morbid height and weight on the survival
of breast cancer patients. Br. J. Cancer 1990, 62, 299–303.
41. Caan, B. J.; Kwan, M. L.; Hartzell, G.; Castillo, A.; Slattery, M.L.; Sternfeld, B.; Weltzien, E.
Pre-diagnosis body mass index, post-diagnosis weight change, and prognosis among women with
early stage breast cancer. Cancer Causes Contr. 2008, 19, 1319–1328.
Cancers 2010, 2
42. Chen, X.; Lu, W.; Zheng, W.; Gu, K.; Chen, Z.; Zheng, Y.; Shu, X.O. Obesity and weight change
in relation to breast cancer survival. Breast Cancer Res. Treat. 2010, DOI
43. Dignam, J.J.; Wieand, K.; Johnson, K.A.; Raich, P.; Anderson, S.J.; Somkin, C.; Wickerham,
D.L. Effects of obesity and race on prognosis in lymph node-negative, estrogen receptor-negative
breast cancer. Breast Cancer Res. Treat. 2006, 97, 245–254.
44. Kyogoku, S.; Hirohata, T.; Takeshita, S.; Nomura, Y.; Shigematsu, T.; Horie, A. Survival of
breast-cancer patients and body size indicators. Int. J. Cancer 1990, 46, 824–831.
45. Rose, D.P.; Haffner, S.M.; Baillargeon, J. Adiposity, the metabolic syndrome, and breast cancer
in African-American and white American women. Endocr. Rev. 2007, 28,763–777.
46. Gu, K.; Chen, X.; Zheng, Y.; Chen, Z.; Zheng, W.; Lu, W.; Shu, X.O. Weight change patterns
among breast cancer survivors: results from the Shanghai breast cancer survival study. Cancer
Causes Contr. 2009, DOI 10.1007/s10552-009-9491-z.
47. Demark-Wahnefried, W.; Rimer, B.K.; Winer, E.P. Weight gain in women diagnosed with breast
cancer. J. Am. Diet Assoc. 1997, 97, 519–526, 529, 527–528.
48. Nichols, H.B.; Trentham-Dietz, A.; Egan, K.M.; Titus-Ernstoff, L.; Holmes, M.D.; Bersch, A.J.;
Holick, C.N.; Hampton, J.M.; Stampfer, M.J.; Willett, W.C.; et al. Body mass index before and
after breast cancer diagnosis: associations with all-cause, breast cancer, and cardiovascular
disease mortality. Cancer Epidemiol. Biomarkers Prev. 2009, 18, 1403–1409.
49. Loprinzi, C.L.; Athmann, L.M.; Kardinal, C.G.; O'Fallon, J.R.; See, J.A.; Bruce, B.K.; Dose,
A.M.; Miser, A.W.; Kern, P.S.; Tschetter, L.K.; Rayson, S. Randomized trial of dietician
counseling to try to prevent weight gain associated with breast cancer adjuvant chemotherapy.
Oncology 1996, 53, 228–232.
50. Demark-Wahnefried, W.; Peterson, B.L.; Winer, E.P.; Marks, L.; Aziz, N.; Marcom, P. K.;
Blackwell, K.; Rimer, B.K. Changes in weight, body composition, and factors influencing energy
balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J. Clin.
Oncol. 2001, 19, 2381–2389.
51. Dal Maso, L.; Zucchetto, A.; Talamini, R.; Serraino, D.; Stocco, C.F.; Vercelli, M.; Falcini, F.;
Franceschi, S. Effect of obesity and other lifestyle factors on mortality in women with breast
cancer. Int. J. Cancer 2008, 123, 2188–2194.
52. Zhang, S.; Folsom, A.R.; Sellers, T.A.; Kushi, L.H.; Potter, J.D. Better breast cancer survival for
postmenopausal women who are less overweight and eat less fat. The Iowa Women's Health
Study. Cancer 1995, 76, 275–283.
53. Deglise, C.; Bouchardy, C.; Burri, M.; Usel, M.; Neyroud-Caspar, I.; Vlastos, G.; Chappuis, P.O.;
Ceschi, M.; Ess, S.; Castiglione, M.; et al. Impact of obesity on diagnosis and treatment of breast
cancer. Breast Cancer Res. Treat. 2010, 120, 185–193.
54. Kirschner, M.A.; Samojlik, E.; Drejka, M.; Szmal, E.; Schneider, G.; Ertel, N.
Androgen-estrogen metabolism in women with upper body versus lower body obesity. J. Clin.
Endocrinol. Metab. 1990, 70, 473–479.
55. Kaye, S.A.; Folsom, A.R.; Soler, J.T.; Prineas, R.J.; Potter, J.D. Associations of body mass and
fat distribution with sex hormone concentrations in postmenopausal women. Int. J. Epidemiol.
1991, 20, 151–156.
Cancers 2010, 2
56. Ballard-Barbash, R. Anthropometry and breast cancer. Body size--a moving target. Cancer 1994,
57. Stoll, B.A.; Secreto, G. New hormone-related markers of high risk to breast cancer. Ann. Oncol.
1992, 3, 435–438.
58. Bruning, P.F. Endogenous estrogens and breast cancer a possible relationship between body fat
distribution and estrogen availability. J. Steroid. Biochem. 1987, 27, 487–492.
59. Stoll, B.A. Obesity and breast cancer. Int. J. Obes. Relat. Metab. Disord. 1996, 20, 389–392.
60. Hollmann, M.; Runnebaum, B.; Gerhard, I. Impact of waist-hip-ratio and body-mass-index on
hormonal and metabolic parameters in young, obese women. Int. J. Obes. Relat. Metab. Disord.
1997, 21, 476–483.
61. Sant, M.; Francisci, S.; Capocaccia, R.; Verdecchia, A.; Allemani, C.; Berrino, F. Time trends of
breast cancer survival in Europe in relation to incidence and mortality. Int. J. Cancer 2006, 119,
62. Kanai, Y. Alterations of DNA methylation and clinicopathological diversity of human cancers.
Pathol. Int. 2008, 58, 544–558.
63. Hussain, S.P.; Harris, C.C. Inflammation and cancer: an ancient link with novel potentials. Int. J.
Cancer 2007, 121, 2373–2380.
64. Choi, A.O.; Brown, S.E.; Szyf, M.; Maysinger, D. Quantum dot-induced epigenetic and
genotoxic changes in human breast cancer cells. J. Mol. Med. 2008, 86, 291–302.
65. Osin, P.; Lu, Y.J.; Stone, J.; Crook, T.; Houlston, R.S.; Gasco, M.; Gusterson, B.A.; Shipley, J.
Distinct genetic and epigenetic changes in medullary breast cancer. Int. J. Surg. Pathol. 2003, 11,
66. Martens, J.W.; Margossian, A.L.; Schmitt, M.; Foekens, J.; Harbeck, N. DNA methylation as a
biomarker in breast cancer. Future Oncol. 2009, 5, 1245–1256.
67. Dworkin, A.M.; Huang, T H.; Toland, A.E. Epigenetic alterations in the breast: Implications for
breast cancer detection, prognosis and treatment. Semin. Cancer Biol. 2009, 19, 165–171.
68. Reaven, G.M.; Laws, A. Insulin resistance, compensatory hyperinsulinaemia, and coronary heart
disease. Diabetologia 1994, 37, 948–952.
69. Berrino, F.; Pasanisi, P.; Bellati, C.; Venturelli, E.; Krogh, V.; Mastroianni, A.; Berselli, E.; Muti,
P.; Secreto, G. Serum testosterone levels and breast cancer recurrence. Int. J. Cancer 2005, 113,
70. Goodwin, P.J.; Ennis, M.; Pritchard, K.I.; Trudeau, M.E.; Koo, J.; Madarnas, Y.; Hartwick, W.;
Hoffman, B.; Hood, N. Fasting insulin and outcome in early-stage breast cancer: results of a
prospective cohort study. J. Clin. Oncol. 2002, 20, 42–51.
71. Bozcuk, H.; Uslu, G.; Samur, M.; Yildiz, M.; Ozben, T.; Ozdogan, M.; Artac, M.; Altunbas, H.;
Akan, I.; Savas, B. Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin
correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy.
Cytokine 2004, 27, 58–65.
72. Pollak, M.N.; Chapman J.W.; Shepherd L.; Meng D.; Richardson P.; Wilson C.; Orme B.;
Pritchard K.I. Insulin resistance, estimated by serum C-peptide level, is associated with reduced
event-free survival for postmenopausal women in NCIC CTG MA. 14 adjuvant breast cancer trial.
J. Clin. Oncol. 2006, 24, 524.
Cancers 2010, 2
73. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314.
74. Menon, R.K.; Sperling, M.A. Insulin as a growth factor. Endocrinol. Metab. Clin. North Am.
1996, 25, 633–647.
75. Belfiore, A.; Frittitta, L.; Costantino, A.; Frasca, F.; Pandini, G.; Sciacca, L.; Goldfine, I.D.;
Vigneri, R. Insulin receptors in breast cancer. Ann. N. Y. Acad. Sci. 1996, 784, 173–188.
76. Papa, V.; Belfiore, A. Insulin receptors in breast cancer: biological and clinical role.
J. Endocrinol. Invest. 1996, 19, 324–333.
77. Milazzo, G.; Giorgino, F.; Damante, G.; Sung, C.; Stampfer, M.R.; Vigneri, R.; Goldfine, I.D.;
Belfiore, A. Insulin receptor expression and function in human breast cancer cell lines. Cancer
Res. 1992, 52, 3924–3930.
78. Cullen, K.J.; Yee, D.; Sly, W.S.; Perdue, J.; Hampton, B.; Lippman, M.E.; Rosen, N. Insulin-like
growth factor receptor expression and function in human breast cancer. Cancer Res. 1990, 50,
79. Mulligan, A.M.; O'Malley, F. P.; Ennis, M.; Fantus, I.G.; Goodwin, P.J. Insulin receptor is an
independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res.
Treat. 2007, 106, 39–47.
80. Papa, V.; Pezzino, V.; Costantino, A.; Belfiore, A.; Giuffrida, D.; Frittitta, L.; Vannelli, G.B.;
Brand, R.; Goldfine, I.D.; Vigneri, R. Elevated insulin receptor content in human breast cancer.
J. Clin. Invest. 1990, 86, 1503–1510.
81. Mathieu, M.C.; Clark, G.M.; Allred, D.C.; Goldfine, I.D.; Vigneri, R. Insulin receptor expression
and clinical outcome in node-negative breast cancer. Proc. Assoc. Am. Physicians 1997, 109,
82. Haffner, S.M.; Valdez, R.A. Endogenous sex hormones: impact on lipids, lipoproteins, and
insulin. Am. J. Med. 1995, 98, 40–47.
83. Gustafsson, J.A.; Warner, M. Estrogen receptor beta in the breast: role in estrogen responsiveness
and development of breast cancer. J. Steroid. Biochem. Mol. Biol. 2000, 74, 245–248.
84. Holden, R.J. The estrogen connection: the etiological relationship between diabetes, cancer,
rheumatoid arthritis and psychiatric disorders. Med. Hypotheses 1995, 45, 169–189.
85. Kolm, V.; Sauer, U.; Olgemoller, B.; Schleicher, E.D. High glucose-induced TGF-beta 1
regulates mesangial production of heparan sulfate proteoglycan. Am. J. Physiol. 1996, 270,
86. Lewitt, M.S. Role of the insulin-like growth factors in the endocrine control of glucose
homeostasis. Diabetes Res. Clin. Pract. 1994, 23, 3–15.
87. Reaven, G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988,
88. Clemmons, D.R.; Underwood, L.E. Nutritional regulation of IGF-I and IGF binding proteins.
Annu. Rev. Nutr. 1991, 11, 393–412.
89. Le, R.D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth
factors. N. Engl. J. Med. 1997, 336, 633–640.
90. Lipworth, L.; Adami, H.O.; Trichopoulos, D.; Carlstrom, K.; Mantzoros, C. Serum steroid
hormone levels, sex hormone-binding globulin, and body mass index in the etiology of
postmenopausal breast cancer. Epidemiology 1996, 7, 96–100.