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The molecular mechanisms between metabolic syndrome and breast cancer
Accepted Manuscript The molecular mechanisms between metabolic syndrome and breast cancer Yi Chen, Ya-yuan Wen, Zhi-rong Li, Dong-lin Luo, Xiao-hua Zhang PII:
S0006-291X(16)30223-6
DOI:
10.1016/j.bbrc.2016.02.034
Reference:
YBBRC 35337
To appear in:
Biochemical and Biophysical Research Communications
Received Date: 11 January 2016 Accepted Date: 10 February 2016
Please cite this article as: Y. Chen, Y.-y. Wen, Z.-r. Li, D.-l. Luo, X.-h. Zhang, The molecular mechanisms between metabolic syndrome and breast cancer, Biochemical and Biophysical Research Communications (2016), doi: 10.1016/j.bbrc.2016.02.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The molecular mechanisms between metabolic syndrome
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and breast cancer
Department of General Surgery (Breast, Thyroid and Vascular Suerery), Daping
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Yi Chen1, Ya-yuan Wen1, Zhi-rong Li1, Dong-lin Luo1, Xiao-hua Zhang1,*
Hospital of the Third Military Medical University, Chongqing, 400042, China
* Corresponding Author:
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Xiao-hua Zhang, Department of General Surgery (Breast, Thyroid and Vascular Suerery), Daping Hospital of the Third Military Medical University, Chongqing,
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400042, China, Tel: 86-13637970778, Email: [email protected].
ACCEPTED MANUSCRIPT Metabolic syndrome, which is extremely common in developed and some developing countries, is a clustering of at least three of five of the following medical conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein levels. It has been
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proved that there is a strong association between metabolic syndrome and breast cancer. Metabolic syndrome could increase the risk of breast cancer and influence the prognosis of the breast cancer patients. Some characteristic of metabolic syndrome such as obesity and lack of physical exercise are all risk factors for developing breast
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cancer. The metabolic syndrome mainly include obesity, type 2 diabetes, hypercholesterolemia and nonalcoholic fatty liver disease, and each of them impacts
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the risk of breast cancer and the prognosis of the breast cancer patients in different ways. In this Review, we focus on recently uncovered aspects of the immunological and molecular mechanisms that are responsible for the development of this highly prevalent and serious disease. These studies bring new insight into the complex associations between metabolic syndrome and breast cancer and have led to the
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development of novel therapeutic strategies that might enable a personalized approach in the management of this disease.
Keywords: Metabolic syndrome, breast cancer, obesity, type 2 diabetes, nonalcoholic
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fatty liver disease.
ACCEPTED MANUSCRIPT Breast cancer (BC) is perhaps the most-studied malignancy in the world. Some 1.7 million women were diagnosed with the disease in 2012, making it a global priority [1]. Although the research on the diagnosis and treatment of BC have been received intense attention, there are still some questions needed to be answered, such as which
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cancers need to be treated, who should be having mammograms, and how often, what are the possibilities, and limits, of immunotherapy, and what are the risk factors for the disease [2].
Several studies have reported that BC is associated with metabolic syndrome (MS)
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and insulin resistance (IR) [3,4]. It is also reported that MS is associated with a modestly increased risk of second breast cancer events and BC-specific mortality that
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is concerning due to the growing population of BC survivors and prevalence of MS risk factors [5]. Recent study shows that within the U.S. there are more than 2.4 million BC survivors with a 5-year survival rate of 88.6%. These survivors are at an increased risk of cancer recurrence, comorbidities such as diabetes, osteoporosis and cardiovascular disease (CVD) [6,7]. The MS is defined by a group of metabolic risk
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factors that have a tendency to cluster together in one individual-obesity, hypertension, dyslipidaemia and IR. These factors have been associated with several chronic diseases, especially CVD, type 2 diabetes and non-alcoholic fatty liver disease
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(NAFLD) separately and jointly [8].
MS, a spectrum of conditions including abdominal obesity, IR, atherogenic dyslipidemia and hypertension, has been related to the risk of BC worldwide [9]. The
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ORDET cohort showed that after menopause the presence of MS is associated with a 2.6 times higher BC risk compared with the absence of any components of MS. Women with MS (3 or more components) had a significantly higher risk of BC than women without MS (less than 3 components): HR 1.58 [10]. A recent meta-analysis showed that the risk of BC is 1.56 times higher in postmenopausal women with MS than in women without MS [11]. Bhandari R et al. also suggested that positive association was observed between MS and BC risk (RR: 1.47, 95% CI, 1.15-1.87; z = 3.13; p = 0.002; Q = 26.28, p = 0.001; I (2) = 69.55%). MS is associated with increased BC risk in adult women [12]. Berrino F et al. suggested that the presence of
ACCEPTED MANUSCRIPT MS was a major determinant of the occurrence of new BC events in a cohort of 2,092 women patients operated for BC on average 1.7 years before recruitment. The risk of distant metastases was more than double in patients with MS than in patients without any dismetabolic traits [13].
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Given that metabolic dysregulation may affect risk for recurrence of BC and onset of additional chronic disease, investigation into effective interventions for reducing MS in BC survivors is also a badly needed area of research. However, the mechanisms by which MS affects prognosis of BC patients are not clear, which might
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include higher sex hormone levels, higher levels of insulin and insulin-like growth factor I (IGF-I), and chronic inflammatory status [14].
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In this review, we will discuss how the MS such as obesity, type 2 diabetes, hypercholesterolemia and NAFLD may contribute to the development of BC growth and influence the prognosis of BC patients mainly focusing on the linking molecular mechanisms between the MS and BC (Fig 1). Obesity and breast cancer
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Obesity, particularly abdominal obesity, is associated with IR and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes. Although many metabolic abnormalities occur with obesity and type 2 diabetes, IR and
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hyperinsulinemia appear to be central to these conditions and may contribute to the dyslipidemia and altered levels of circulating estrogens. It has been recognized in 2001 that excess body weight increases the risk of BC in
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postmenopausal women, and there is a closely association between the obesity and the risk of BC [15,16]. Obesity and carcinogenesis share 2 properties in common. On the one hand, they involve inflammatory pathways, and on the other hand, they are characterized by dysregulated metabolism [17,18]. Importantly, obesity can promote carcinogenesis through directly and indirectly pathways. The direct pathway is that the aromatase enzyme synthesizes estrogens in adipose tissue from circulating androgens, then stimulating breast cells to proliferate, and the indirect pathway is that the presence of visceral obesity impacts on cell sensitivity to insulin activity and increases synthesis of leptin by adipose tissue, which will resulting in a
ACCEPTED MANUSCRIPT hyperinsulinemic state and disordered mitogenic and antiapoptotic effects [19,20]. A study from U.S in 2009 found that among women who gained weight after BC diagnosis, each 5-kg gain was associated with a 13% increase in BC-specific mortality, which concluded that greater post-diagnosis body mass index and weight gain were
offer women a greater chance of surviving BC [21].
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associated with higher rates of BC mortality, hence avoidance of weight gain may
It has been deemed that obesity may affect BC prognosis through several ways. Firstly, obese women are often diagnosed with more advanced disease, such as
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NAFLD and Type 2 diabetes, which will probably increase the risk of liver and renal related mortality [22]. Secondly, BC progression is definitely under natural
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immunosurveillance and accumulating evidence indicates that the negative impact of obesity and MS on the function of immune system may play an aggravating role as well [23]. Thirdly, treatment may be less effective than among non-obese women affected by obesity [24]. Finally, obesity affects the level of various hormones including estrogen, insulin, and the IGF system and tumor progression [25]. It is
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reported that the increase in BC risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens. Higher circulating endogenous estrogen increases the IR of postmenopausal BC approximately two fold
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[26].
Estrogens play an essential role in the progression of breast tumors. The effects of estrogen in the breast are mediated through estrogen receptor α (ERα), ERβ, and the G
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protein-coupled estrogen receptor (GPER) [27]. Classically, estrogen signaling occurs through the binding of estrogen to the ERα, leading to dimerization of ERα, translocation to the nucleus, and the regulation of gene transcription. The ER complex consisted of ERα and ERβ binds to ER response elements in the promoter regions of various ER-regulated genes, and gene transcription may be activated or repressed depending on the activators and repressors in the ER complex [28,29]. The ER is a primary target for BC treatment. The ER status of a tumor has two conditions, which are closely associated with therapeutic method. The ER status of a tumor is designated as ER negative if there is less than 10% nuclear staining for ERα
ACCEPTED MANUSCRIPT on immunohistochemistry. However, “ER-negative” BC cells may still express ERα at low level. In addition, ERβ expression is higher in some “ER-negative” BC cell lines than in ER-positive cell lines. Consequently, in breast cancers traditionally considered as ER negative and unresponsive to hormone therapy, the ERs may play a role in cell
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signaling, growth, and survival [30]. As BC progresses to estrogen-independent growth, the IGF-IR and the ER interact in synergistic cross-talk mechanisms, which result in enhanced activation of both receptors' signaling cascades. Cross talk between the IGF-IR and ER signaling pathway has been hypothesized as a mechanism of
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resistance to hormone receptor-targeted therapy [31]. IGF-II is critical in BC progression and its actions are mediated by the IGF-IR. Gene expression profiling of
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MCF-7 cells treated with IGF-I and estrogen suggested that estrogen and IGF-I signaling result in the repression of many common target genes, and for many of the genes, the estrogen- and IGF-I-mediated repression occurred independent of IGF-IR and ER signaling [32]. Therefore, because of this cross talk and independent regulation of common genes, it has been hypothesized that inhibiting IGF-IR
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signaling and ER signaling would prevent BC resistance to hormone therapy, which might be an effective way to treat the BC. Altogether, these studies above indicated that there is a closely relationship between obesity and BC, and obesity can aggravate
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the prognosis of BC patients through various pathways. Type 2 diabetes and breast cancer IR and hyperinsulinemia are essential to the pathogenesis of type 2 diabetes, and
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several studies have focused specifically on these aspects associated with the development of BC. A case-cohort study nested in a multicentre italian cohort indicated that presence of MS was associated with increased BC risk in postmenopausal women. Among the MS, high fasting glucose was significantly associated with increased BC risk in all women [33]. The insulin is best known for its important role it plays as a homeostatic regulator of blood glucose, gluconeogenesis, and fatty acid metabolism in metabolic tissues such as the skeletal muscle, adipose tissue and liver. Recently several epidemiological studies explore the connection between type 2
ACCEPTED MANUSCRIPT diabetes and the incidence, recurrence, and mortality of BC in women. One of the studies conducted by Cleveland RJ. et al. indicated that postmenopausal women with diabetes were at increased risk of developing BC [odds ratio (OR) = 1.35], as were those who were not of white race (such as the black race and the yellow race)
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regardless of menopausal status [OR = 3.89]. Among women, diabetes was associated with a modestly increased risk of death from all causes, an association that was stronger in women who were obese at BC diagnosis [34]. Their findings suggest that diabetes may increase incidence of BC in older women and non-whites, and mortality
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due to all causes [34]. In a study from Asia, a lower breast cancer-specific survival rate has been reported for diabetic versus nondiabetic women over 40 years of age at
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both 2 and 5 years postsurgery, which suggest that type 2 diabetes is an independent predictor of lower breast cancer-specific survival (BCS) and overall survival (OS) rates in Asian patients with early-stage BC [35].
IR is a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. When the body produces insulin under conditions of IR, the cells
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in the body are resistant to the insulin and are unable to use it effectively, leading to hyperglycemia and hyperinsulinemia. IR is usually caused by defects in the IR signaling pathways which mediate glucose uptake and is a central characteristic of
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both the MS and type 2 diabetes. Insulin and the IGF family classically comprise ligands including insulin, IGF-I and IGF-II. There are three receptors, the insulin receptor, the IGF-I receptor (IGF-IR) and the IGF-II receptor (IGF-IIR) [36]. It is
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deemed that hyperglycemia and hyperinsulinemia could potentially impact cancer progression through several mechanisms. First, hyperinsulinemia increases IGF-I bioavailability by increasing hepatic growth hormone receptor expression, leading to growth hormone mediated increases in IGF-I production by the liver and repressing hepatic production of IGF-binding proteins (IGFBP)-1 and -2. This increase in IGF-I could lead to increased signaling via insulin receptor isoform-A/IGF-IR hybrids and the IGF-IR. Second, insulin has a high affinity for insulin receptor isoform-A and could promote cell proliferation through its cognate receptor [37,38]. Mammographic density, which reflects cell proliferation activity in the breast, can
ACCEPTED MANUSCRIPT hamper the detection of BC with a mammogram. Reduced mammographic sensitivity to BC was observed in women with dense breast tissue compared with those with fattier breast tissue, due to the masking effect of dense breast tissue. There is emerging evidence that in a large sample of Korean women, IR was associated with
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mammographic dense breast, which demonstrated that IR, as a potentially modifiable risk factor, may increase BC risk, possibly through high mammographic density [39]. Other factors such as physical activity, alcohol consumption and diet, all of which affect IR, may also influence BC risk through mammographic density [40-42].
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Although several pathways between type 2 diabetes and BC have been identified, the precise mechanism of each pathway and the role molecules involved in the process
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play remains to be further investigated.
Other types of diseases of metabolic syndrome and breast cancer Dyslipidemia has been associated with an increased risk for developing cancer such as BC growth and metastasis [43]. It has been reported that hypercholesterolemia affects mammary tumor growth and metastasis [44]. Because apolipoprotein E (ApoE)
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glycoprotein functions as a regulator of plasma lipid levels and has a role in the uptake of lipids into different tissues and in delivering cholesterol and triglycerides into cells, Alikhani et al. used the ApoE knockout (ApoE-/-) mice, which exhibit
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marked dyslipidemia such as elevated circulating cholesterol and triglyceride levels, to explore the role of dyslipidemia in BC growth and metastasis. They found that the hypercholesterolemic milieu in the ApoE-/- mice is a favorable setting for mammary
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tumor growth and metastasis, and they deemed that cholesterol can promote tumor growth and metastasis in BC through PI3K/Akt signal pathway, and thus suggest that reducing total cholesterol levels may be an important therapeutic modality in the prevention and treatment of BC [44]. It has been proven that matrix metallopeptidase 9 (MMP-9) promotes metastasis of the cancer cells. The effect of MMP-9 on the malignant progression of invasive BC promoted by membrane progesterone receptorα (mPRα) has been widely investigated, and it is recently reported that mPRα was a major marker of harmful prognosis and it promoted the expression of MMP-9 during invasion to the local lymph nodes through the pathway of PI3K/Akt in the invasive
ACCEPTED MANUSCRIPT BC [45]. NAFLD, which has become the most common cause of chronic liver disease in the developed world, is projected to become the leading cause of liver transplantation in the USA by 2020 [46]. Selective estrogen receptor modulator (SERM)-associated
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NAFLD might be related to treatment efficacy in patients with BC because of circulating estrogen antagonism. One study aimed to investigate the relationship between NAFLD and survival outcomes in patients with BC treated with tamoxifen, finally they concluded that SERM-associated NAFLD was independently associated
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with improved disease-free survival (DFS) and might be useful for predicting treatment responses in BC patients treated with SERMs [47]. Some inflammatory
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factors have been suggested to contribute to the increased risk of BC progression and mortality. For instance, the NF-κB signaling pathway has been reported to take part in growth of anti-estrogen-resistant BC cells using an macrophage chemotactic factor (MCF) 7-derived cell model, whereas NF-κB signaling pathway is also activated durning the state of NAFLD [48,49]. Although it has been acknowledged that there is
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a relationship between NAFLD and BC, the data from clinical observation and basic research is still insufficient. Additional studies are needed to explore the exact mechanism and signal pathway that are responsible for the effects of NAFLD on BC.
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Concluding remarks
MS has become a major public health problem worldwide and represents a common clinical condition in countries with a high incidence of obesity and western
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dietary patterns [5]. Of all the components of MS, obesity seems to be the essential initial factor which provides a direct link between inflammation and dysregulated metabolism and has been the etiology of numerous cancers such as BC. In addition, obesity plays an important role in the regulation of estrogen biosynthesis in adipose tissue. The role of MS especially obesity in postmenopausal BC must be seen because estrogen plays a dominant role in driving this disease [14]. Due to a higher prevalence of MS in BC survivors, lifestyle interventions are badly needed to prevent chronic diseases associated with obesity. BC clinics should consider offering BC patients with MS personalised nutritional advice in order to reduce MS
ACCEPTED MANUSCRIPT parameters. Increasing exercise adherence is a necessary target for further research in obese BC survivors. The treatments such as surgery, chemotherapy, radiation therapy, and endocrine therapy usually result in adverse effects. One important consequence of these adverse effects is a profound decline in physical activity. This is particularly
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essential because physical activity is thought to lower the risk of cancer recurrence and mortality [50]. It is reported that metabolic disease-related effects of resistance and aerobic exercise training and inform intervention programs that will optimally improve physiological and psychosocial health during cancer survivorship, and that
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are ultimately aimed at improving prognosis of the BC patients [51]. Guinan E et al. examined the effect of an 8-week aerobic exercise intervention on several of these
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outcomes, including body composition, the MS and physical activity in BC survivors 2-6 months post-chemotherapy. They found that those who adhered to >90 % of the supervised exercise class showed a significant decrease in waist circumference although did not elicit significant improvements in biomarkers of BC risk [52]. More importantly, it is generally recognized that regular and persistent exercise after cancer
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diagnosis, even at low-to-moderate intensity level, decrease the prevalence of MS among long-term BC survivors, and then improve the prognosis of the long-term BC survivors [53].
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In summary, we should know which women are susceptible to BC and why those women have got BC, which would illuminate the root causes of the disease and lead to new approaches for prevention and treatment. Different molecular pathways
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involved in MS and breast carcinogenesis are expected to be clearly confirmed, which would also help us to integrate them and find pivotal treatment targets.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Diseases of metabolic syndrome influencing the breast cancer through different signaling pathways. Metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal obesity, elevated blood pressure,
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elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein levels. The metabolic syndrome mainly include obesity, type 2 diabetes, hypercholesterolemia and nonalcoholic fatty liver disease, and each of them impacts the risk of breast cancer through different signaling pathways. FPG, fasting plasma
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glucose; TG, triglyceride; BP, blood pressure; HDL, high density lipoprotein; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; IGF, insulin-like
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growth factor; ER, estrogen receptor; IR, insulin resistance.
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Highlights 1.
Breast cancer is perhaps the most-studied malignancy in the world. Some 1.7 million women were diagnosed with the disease in 2012, making it a global priority. Although the research on the diagnosis and treatment of breast cancer has
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been received intense attention, there are still some questions needed to be answered. 2.
Obesity, particularly abdominal obesity, is associated with insulin resistance and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes.
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It has been deemed that obesity may affect breast cancer prognosis through several ways.
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Insulin resistance and hyperinsulinemia are essential to the pathogenesis of type 2 diabetes, and several studies have focused specifically on these aspects associated
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with the development of breast cancer.
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3.
S0006-291X(16)30223-6
DOI:
10.1016/j.bbrc.2016.02.034
Reference:
YBBRC 35337
To appear in:
Biochemical and Biophysical Research Communications
Received Date: 11 January 2016 Accepted Date: 10 February 2016
Please cite this article as: Y. Chen, Y.-y. Wen, Z.-r. Li, D.-l. Luo, X.-h. Zhang, The molecular mechanisms between metabolic syndrome and breast cancer, Biochemical and Biophysical Research Communications (2016), doi: 10.1016/j.bbrc.2016.02.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The molecular mechanisms between metabolic syndrome
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and breast cancer
Department of General Surgery (Breast, Thyroid and Vascular Suerery), Daping
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Yi Chen1, Ya-yuan Wen1, Zhi-rong Li1, Dong-lin Luo1, Xiao-hua Zhang1,*
Hospital of the Third Military Medical University, Chongqing, 400042, China
* Corresponding Author:
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Xiao-hua Zhang, Department of General Surgery (Breast, Thyroid and Vascular Suerery), Daping Hospital of the Third Military Medical University, Chongqing,
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400042, China, Tel: 86-13637970778, Email: [email protected].
ACCEPTED MANUSCRIPT Metabolic syndrome, which is extremely common in developed and some developing countries, is a clustering of at least three of five of the following medical conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein levels. It has been
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proved that there is a strong association between metabolic syndrome and breast cancer. Metabolic syndrome could increase the risk of breast cancer and influence the prognosis of the breast cancer patients. Some characteristic of metabolic syndrome such as obesity and lack of physical exercise are all risk factors for developing breast
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cancer. The metabolic syndrome mainly include obesity, type 2 diabetes, hypercholesterolemia and nonalcoholic fatty liver disease, and each of them impacts
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the risk of breast cancer and the prognosis of the breast cancer patients in different ways. In this Review, we focus on recently uncovered aspects of the immunological and molecular mechanisms that are responsible for the development of this highly prevalent and serious disease. These studies bring new insight into the complex associations between metabolic syndrome and breast cancer and have led to the
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development of novel therapeutic strategies that might enable a personalized approach in the management of this disease.
Keywords: Metabolic syndrome, breast cancer, obesity, type 2 diabetes, nonalcoholic
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fatty liver disease.
ACCEPTED MANUSCRIPT Breast cancer (BC) is perhaps the most-studied malignancy in the world. Some 1.7 million women were diagnosed with the disease in 2012, making it a global priority [1]. Although the research on the diagnosis and treatment of BC have been received intense attention, there are still some questions needed to be answered, such as which
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cancers need to be treated, who should be having mammograms, and how often, what are the possibilities, and limits, of immunotherapy, and what are the risk factors for the disease [2].
Several studies have reported that BC is associated with metabolic syndrome (MS)
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and insulin resistance (IR) [3,4]. It is also reported that MS is associated with a modestly increased risk of second breast cancer events and BC-specific mortality that
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is concerning due to the growing population of BC survivors and prevalence of MS risk factors [5]. Recent study shows that within the U.S. there are more than 2.4 million BC survivors with a 5-year survival rate of 88.6%. These survivors are at an increased risk of cancer recurrence, comorbidities such as diabetes, osteoporosis and cardiovascular disease (CVD) [6,7]. The MS is defined by a group of metabolic risk
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factors that have a tendency to cluster together in one individual-obesity, hypertension, dyslipidaemia and IR. These factors have been associated with several chronic diseases, especially CVD, type 2 diabetes and non-alcoholic fatty liver disease
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(NAFLD) separately and jointly [8].
MS, a spectrum of conditions including abdominal obesity, IR, atherogenic dyslipidemia and hypertension, has been related to the risk of BC worldwide [9]. The
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ORDET cohort showed that after menopause the presence of MS is associated with a 2.6 times higher BC risk compared with the absence of any components of MS. Women with MS (3 or more components) had a significantly higher risk of BC than women without MS (less than 3 components): HR 1.58 [10]. A recent meta-analysis showed that the risk of BC is 1.56 times higher in postmenopausal women with MS than in women without MS [11]. Bhandari R et al. also suggested that positive association was observed between MS and BC risk (RR: 1.47, 95% CI, 1.15-1.87; z = 3.13; p = 0.002; Q = 26.28, p = 0.001; I (2) = 69.55%). MS is associated with increased BC risk in adult women [12]. Berrino F et al. suggested that the presence of
ACCEPTED MANUSCRIPT MS was a major determinant of the occurrence of new BC events in a cohort of 2,092 women patients operated for BC on average 1.7 years before recruitment. The risk of distant metastases was more than double in patients with MS than in patients without any dismetabolic traits [13].
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Given that metabolic dysregulation may affect risk for recurrence of BC and onset of additional chronic disease, investigation into effective interventions for reducing MS in BC survivors is also a badly needed area of research. However, the mechanisms by which MS affects prognosis of BC patients are not clear, which might
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include higher sex hormone levels, higher levels of insulin and insulin-like growth factor I (IGF-I), and chronic inflammatory status [14].
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In this review, we will discuss how the MS such as obesity, type 2 diabetes, hypercholesterolemia and NAFLD may contribute to the development of BC growth and influence the prognosis of BC patients mainly focusing on the linking molecular mechanisms between the MS and BC (Fig 1). Obesity and breast cancer
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Obesity, particularly abdominal obesity, is associated with IR and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes. Although many metabolic abnormalities occur with obesity and type 2 diabetes, IR and
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hyperinsulinemia appear to be central to these conditions and may contribute to the dyslipidemia and altered levels of circulating estrogens. It has been recognized in 2001 that excess body weight increases the risk of BC in
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postmenopausal women, and there is a closely association between the obesity and the risk of BC [15,16]. Obesity and carcinogenesis share 2 properties in common. On the one hand, they involve inflammatory pathways, and on the other hand, they are characterized by dysregulated metabolism [17,18]. Importantly, obesity can promote carcinogenesis through directly and indirectly pathways. The direct pathway is that the aromatase enzyme synthesizes estrogens in adipose tissue from circulating androgens, then stimulating breast cells to proliferate, and the indirect pathway is that the presence of visceral obesity impacts on cell sensitivity to insulin activity and increases synthesis of leptin by adipose tissue, which will resulting in a
ACCEPTED MANUSCRIPT hyperinsulinemic state and disordered mitogenic and antiapoptotic effects [19,20]. A study from U.S in 2009 found that among women who gained weight after BC diagnosis, each 5-kg gain was associated with a 13% increase in BC-specific mortality, which concluded that greater post-diagnosis body mass index and weight gain were
offer women a greater chance of surviving BC [21].
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associated with higher rates of BC mortality, hence avoidance of weight gain may
It has been deemed that obesity may affect BC prognosis through several ways. Firstly, obese women are often diagnosed with more advanced disease, such as
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NAFLD and Type 2 diabetes, which will probably increase the risk of liver and renal related mortality [22]. Secondly, BC progression is definitely under natural
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immunosurveillance and accumulating evidence indicates that the negative impact of obesity and MS on the function of immune system may play an aggravating role as well [23]. Thirdly, treatment may be less effective than among non-obese women affected by obesity [24]. Finally, obesity affects the level of various hormones including estrogen, insulin, and the IGF system and tumor progression [25]. It is
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reported that the increase in BC risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens. Higher circulating endogenous estrogen increases the IR of postmenopausal BC approximately two fold
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[26].
Estrogens play an essential role in the progression of breast tumors. The effects of estrogen in the breast are mediated through estrogen receptor α (ERα), ERβ, and the G
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protein-coupled estrogen receptor (GPER) [27]. Classically, estrogen signaling occurs through the binding of estrogen to the ERα, leading to dimerization of ERα, translocation to the nucleus, and the regulation of gene transcription. The ER complex consisted of ERα and ERβ binds to ER response elements in the promoter regions of various ER-regulated genes, and gene transcription may be activated or repressed depending on the activators and repressors in the ER complex [28,29]. The ER is a primary target for BC treatment. The ER status of a tumor has two conditions, which are closely associated with therapeutic method. The ER status of a tumor is designated as ER negative if there is less than 10% nuclear staining for ERα
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signaling, growth, and survival [30]. As BC progresses to estrogen-independent growth, the IGF-IR and the ER interact in synergistic cross-talk mechanisms, which result in enhanced activation of both receptors' signaling cascades. Cross talk between the IGF-IR and ER signaling pathway has been hypothesized as a mechanism of
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resistance to hormone receptor-targeted therapy [31]. IGF-II is critical in BC progression and its actions are mediated by the IGF-IR. Gene expression profiling of
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MCF-7 cells treated with IGF-I and estrogen suggested that estrogen and IGF-I signaling result in the repression of many common target genes, and for many of the genes, the estrogen- and IGF-I-mediated repression occurred independent of IGF-IR and ER signaling [32]. Therefore, because of this cross talk and independent regulation of common genes, it has been hypothesized that inhibiting IGF-IR
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signaling and ER signaling would prevent BC resistance to hormone therapy, which might be an effective way to treat the BC. Altogether, these studies above indicated that there is a closely relationship between obesity and BC, and obesity can aggravate
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the prognosis of BC patients through various pathways. Type 2 diabetes and breast cancer IR and hyperinsulinemia are essential to the pathogenesis of type 2 diabetes, and
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several studies have focused specifically on these aspects associated with the development of BC. A case-cohort study nested in a multicentre italian cohort indicated that presence of MS was associated with increased BC risk in postmenopausal women. Among the MS, high fasting glucose was significantly associated with increased BC risk in all women [33]. The insulin is best known for its important role it plays as a homeostatic regulator of blood glucose, gluconeogenesis, and fatty acid metabolism in metabolic tissues such as the skeletal muscle, adipose tissue and liver. Recently several epidemiological studies explore the connection between type 2
ACCEPTED MANUSCRIPT diabetes and the incidence, recurrence, and mortality of BC in women. One of the studies conducted by Cleveland RJ. et al. indicated that postmenopausal women with diabetes were at increased risk of developing BC [odds ratio (OR) = 1.35], as were those who were not of white race (such as the black race and the yellow race)
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regardless of menopausal status [OR = 3.89]. Among women, diabetes was associated with a modestly increased risk of death from all causes, an association that was stronger in women who were obese at BC diagnosis [34]. Their findings suggest that diabetes may increase incidence of BC in older women and non-whites, and mortality
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due to all causes [34]. In a study from Asia, a lower breast cancer-specific survival rate has been reported for diabetic versus nondiabetic women over 40 years of age at
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both 2 and 5 years postsurgery, which suggest that type 2 diabetes is an independent predictor of lower breast cancer-specific survival (BCS) and overall survival (OS) rates in Asian patients with early-stage BC [35].
IR is a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. When the body produces insulin under conditions of IR, the cells
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in the body are resistant to the insulin and are unable to use it effectively, leading to hyperglycemia and hyperinsulinemia. IR is usually caused by defects in the IR signaling pathways which mediate glucose uptake and is a central characteristic of
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both the MS and type 2 diabetes. Insulin and the IGF family classically comprise ligands including insulin, IGF-I and IGF-II. There are three receptors, the insulin receptor, the IGF-I receptor (IGF-IR) and the IGF-II receptor (IGF-IIR) [36]. It is
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deemed that hyperglycemia and hyperinsulinemia could potentially impact cancer progression through several mechanisms. First, hyperinsulinemia increases IGF-I bioavailability by increasing hepatic growth hormone receptor expression, leading to growth hormone mediated increases in IGF-I production by the liver and repressing hepatic production of IGF-binding proteins (IGFBP)-1 and -2. This increase in IGF-I could lead to increased signaling via insulin receptor isoform-A/IGF-IR hybrids and the IGF-IR. Second, insulin has a high affinity for insulin receptor isoform-A and could promote cell proliferation through its cognate receptor [37,38]. Mammographic density, which reflects cell proliferation activity in the breast, can
ACCEPTED MANUSCRIPT hamper the detection of BC with a mammogram. Reduced mammographic sensitivity to BC was observed in women with dense breast tissue compared with those with fattier breast tissue, due to the masking effect of dense breast tissue. There is emerging evidence that in a large sample of Korean women, IR was associated with
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mammographic dense breast, which demonstrated that IR, as a potentially modifiable risk factor, may increase BC risk, possibly through high mammographic density [39]. Other factors such as physical activity, alcohol consumption and diet, all of which affect IR, may also influence BC risk through mammographic density [40-42].
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Although several pathways between type 2 diabetes and BC have been identified, the precise mechanism of each pathway and the role molecules involved in the process
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play remains to be further investigated.
Other types of diseases of metabolic syndrome and breast cancer Dyslipidemia has been associated with an increased risk for developing cancer such as BC growth and metastasis [43]. It has been reported that hypercholesterolemia affects mammary tumor growth and metastasis [44]. Because apolipoprotein E (ApoE)
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glycoprotein functions as a regulator of plasma lipid levels and has a role in the uptake of lipids into different tissues and in delivering cholesterol and triglycerides into cells, Alikhani et al. used the ApoE knockout (ApoE-/-) mice, which exhibit
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marked dyslipidemia such as elevated circulating cholesterol and triglyceride levels, to explore the role of dyslipidemia in BC growth and metastasis. They found that the hypercholesterolemic milieu in the ApoE-/- mice is a favorable setting for mammary
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tumor growth and metastasis, and they deemed that cholesterol can promote tumor growth and metastasis in BC through PI3K/Akt signal pathway, and thus suggest that reducing total cholesterol levels may be an important therapeutic modality in the prevention and treatment of BC [44]. It has been proven that matrix metallopeptidase 9 (MMP-9) promotes metastasis of the cancer cells. The effect of MMP-9 on the malignant progression of invasive BC promoted by membrane progesterone receptorα (mPRα) has been widely investigated, and it is recently reported that mPRα was a major marker of harmful prognosis and it promoted the expression of MMP-9 during invasion to the local lymph nodes through the pathway of PI3K/Akt in the invasive
ACCEPTED MANUSCRIPT BC [45]. NAFLD, which has become the most common cause of chronic liver disease in the developed world, is projected to become the leading cause of liver transplantation in the USA by 2020 [46]. Selective estrogen receptor modulator (SERM)-associated
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NAFLD might be related to treatment efficacy in patients with BC because of circulating estrogen antagonism. One study aimed to investigate the relationship between NAFLD and survival outcomes in patients with BC treated with tamoxifen, finally they concluded that SERM-associated NAFLD was independently associated
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with improved disease-free survival (DFS) and might be useful for predicting treatment responses in BC patients treated with SERMs [47]. Some inflammatory
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factors have been suggested to contribute to the increased risk of BC progression and mortality. For instance, the NF-κB signaling pathway has been reported to take part in growth of anti-estrogen-resistant BC cells using an macrophage chemotactic factor (MCF) 7-derived cell model, whereas NF-κB signaling pathway is also activated durning the state of NAFLD [48,49]. Although it has been acknowledged that there is
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a relationship between NAFLD and BC, the data from clinical observation and basic research is still insufficient. Additional studies are needed to explore the exact mechanism and signal pathway that are responsible for the effects of NAFLD on BC.
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Concluding remarks
MS has become a major public health problem worldwide and represents a common clinical condition in countries with a high incidence of obesity and western
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dietary patterns [5]. Of all the components of MS, obesity seems to be the essential initial factor which provides a direct link between inflammation and dysregulated metabolism and has been the etiology of numerous cancers such as BC. In addition, obesity plays an important role in the regulation of estrogen biosynthesis in adipose tissue. The role of MS especially obesity in postmenopausal BC must be seen because estrogen plays a dominant role in driving this disease [14]. Due to a higher prevalence of MS in BC survivors, lifestyle interventions are badly needed to prevent chronic diseases associated with obesity. BC clinics should consider offering BC patients with MS personalised nutritional advice in order to reduce MS
ACCEPTED MANUSCRIPT parameters. Increasing exercise adherence is a necessary target for further research in obese BC survivors. The treatments such as surgery, chemotherapy, radiation therapy, and endocrine therapy usually result in adverse effects. One important consequence of these adverse effects is a profound decline in physical activity. This is particularly
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essential because physical activity is thought to lower the risk of cancer recurrence and mortality [50]. It is reported that metabolic disease-related effects of resistance and aerobic exercise training and inform intervention programs that will optimally improve physiological and psychosocial health during cancer survivorship, and that
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are ultimately aimed at improving prognosis of the BC patients [51]. Guinan E et al. examined the effect of an 8-week aerobic exercise intervention on several of these
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outcomes, including body composition, the MS and physical activity in BC survivors 2-6 months post-chemotherapy. They found that those who adhered to >90 % of the supervised exercise class showed a significant decrease in waist circumference although did not elicit significant improvements in biomarkers of BC risk [52]. More importantly, it is generally recognized that regular and persistent exercise after cancer
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diagnosis, even at low-to-moderate intensity level, decrease the prevalence of MS among long-term BC survivors, and then improve the prognosis of the long-term BC survivors [53].
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In summary, we should know which women are susceptible to BC and why those women have got BC, which would illuminate the root causes of the disease and lead to new approaches for prevention and treatment. Different molecular pathways
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involved in MS and breast carcinogenesis are expected to be clearly confirmed, which would also help us to integrate them and find pivotal treatment targets.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Diseases of metabolic syndrome influencing the breast cancer through different signaling pathways. Metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal obesity, elevated blood pressure,
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elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein levels. The metabolic syndrome mainly include obesity, type 2 diabetes, hypercholesterolemia and nonalcoholic fatty liver disease, and each of them impacts the risk of breast cancer through different signaling pathways. FPG, fasting plasma
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glucose; TG, triglyceride; BP, blood pressure; HDL, high density lipoprotein; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; IGF, insulin-like
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growth factor; ER, estrogen receptor; IR, insulin resistance.
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Highlights 1.
Breast cancer is perhaps the most-studied malignancy in the world. Some 1.7 million women were diagnosed with the disease in 2012, making it a global priority. Although the research on the diagnosis and treatment of breast cancer has
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been received intense attention, there are still some questions needed to be answered. 2.
Obesity, particularly abdominal obesity, is associated with insulin resistance and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes.
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It has been deemed that obesity may affect breast cancer prognosis through several ways.
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Insulin resistance and hyperinsulinemia are essential to the pathogenesis of type 2 diabetes, and several studies have focused specifically on these aspects associated
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with the development of breast cancer.
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3.