The risk of developing breast cancer increases with age – 75% of breast cancers are diagnosed over the age of 50 and 37% in women over 65.¹ Accumulating evidence in recent years from research studies supports the emerging hypothesis that metabolic syndrome (MetS) may be an important aetiological factor for the development and progression of cancer. The prevalence of MetS is high and still increasing, in parallel with increasing cancer incidence worldwide.² Postmenopausal women show the highest incidence of breast cancer in the female population and are often affected by MetS, which may be associated with a more aggressive breast cancer.^3,4 Weight gain and the redistribution of fat mass in menopause, particularly the deposition of abdominal fat mass, creates an environment that encourages carcinogenesis and discourages apoptosis. This may explain the increased prevalence of MetS in postmenopausal women and the resultant link with breast cancer risk.^3,5

What is metabolic syndrome?

Metabolic syndrome was first described by Gerald Reaven in 1988 as ‘Syndrome X’ and was suggested to be secondary to insulin resistance. More recently, several clinical criteria have been developed to characterise the syndrome as a clustering of risk factors of metabolic origin. In addition to dyslipidaemia, hypertension, visceral adiposity, insulin resistance and hyperglycaemia, the syndrome carries a prothrombotic state and a pro-inflammatory state. Epidemiological studies suggest a positive association between MetS as a whole, along with many of its individual components, and increased breast cancer risk. The molecular basis for this association remains largely unknown.

Detection criteria have evolved over the past decade, however, there is still no universally accepted definition for MetS. The classification systems correspond with respect to the core components: insulin resistance, central obesity, hypertension and dyslipidaemia. The presence of three or more of these risk factors qualifies for the diagnosis of MetS. Depicted in Table 1 are the criteria for diagnosis of MetS from The World Health Organization (WHO), along with those of the American Heart Association (AHA)/National Heart, Lung and Blood Institute (NHLBI) update of the National Cholesterol Education Program (NCEP) criteria, and the International Diabetes Federation (IDF).

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Metabolic syndrome as an entity in relation to breast cancer

Although several studies have looked at the association between individual components of MetS and breast cancer, only a few have looked at breast cancer risk in relation to MetS considered as a single entity, and despite providing inconsistent results they suggest that MetS may be positively associated with risk.³ In a longitudinal study of MetS and postmenopausal breast cancer risk, the presence of MetS at baseline was not associated with risk. 

However, in time-dependent analyses (particularly the presence of the syndrome three to five years prior to diagnosis) the MetS showed a positive association with breast cancer.⁶ A large case control study⁷ and two nested case control studies^5,8 reported 60-75% increases in postmenopausal breast cancer risk associated with MetS. Published studies on MetS as a single risk factor for breast cancer suggest that when three or more MetS components are evident the risk of breast cancer increases compared to no components.^8-10 Capasso et al⁵ reported that none of the individual MetS features were strong enough to individually influence breast carcinogenesis, however, out of the 63 postmenopausal breast cancer cases associated with MetS, 30% presented three or more MetS features, suggesting that the activation of multiple molecular pathways underlying MetS might induce breast tumorigenesis.

A large prospective study entitled the Metabolic Syndrome and Cancer project (Me-Can), by Bjorge et al,¹¹ investigated the effects of MetS factors and the MetS as an entity on cancer risk. This study was initiated in 2006 and existing long-standing cohorts in Austria, Norway and Sweden were included in the project (n = 290,000 women). Analyses within this study showed that in women above the age of 60 there was an increased risk of breast cancer mortality for the MetS factors combined (RR 1.23, 95% CI: 1.04-1.45) and for the following individual factors: blood pressure and glucose.¹¹

Metabolic syndrome variables in relation to breast cancer

Insulin resistance

Insulin has been implicated in cancer progression due to its mitogenic, anti-apoptotic and pro-angiogenic properties. Hyperinsulinaemia, which induces proliferative tissue abnormalities and results in stimulated DNA synthesis and cell proliferation, may play a role in the aetiology of breast cancer.^12-14

A longitudinal study in 2009 measured serum glucose and insulin in relation to breast cancer. Fasting serum glucose and insulin levels were measured at baseline and at years one, three and six of follow-up and they reported a hazard ratio of 2.2 (95% CI: 1.39-3.53) for incidence of breast cancer in postmenopausal women when comparing the highest baseline insulin concentration group to the lowest group.⁶

A mechanism by which insulin may increase breast cancer risk indirectly is through its effect on the bio-availability of insulin-like growth factor (IGF-1) and increased blood concentrations of oestrogen, androstenedione and testosterone, all of which are usually increased in MetS and possess multiple effects that have been linked to tumour growth and metastasis.^15-17 Thus, IGF-1 may influence breast cancer development by mediating growth hormone and regulating cell growth, differentiation, apoptosis and transformation in different tissues, including breast tissue.

Numerous studies have related serum C-peptide levels, which are a reliable marker of insulin secretion, to the risk of breast cancer. A 2011 study of 604 women diagnosed with stages I-IIIA breast cancer in the Health, Eating, Activity and Lifestyle (HEAL) study measured serum C-peptide levels three years after diagnosis. They noted that an increased C-peptide concentration of 1ng/mL was associated with a 35% increased risk of death from breast cancer.¹⁴ This positive association between C-peptide and breast cancer mortality was greater in certain subgroups, such as women with type 2 diabetes, women with a BMI > 25kg/m², women with a higher stage of disease and women with oestrogen receptor-positive tumours. 

Similarly, Keinan-Boker et al¹⁸ and Hirose et al¹⁹ both showed a positive association between C-peptide and breast cancer risk among postmenopausal women. Together these data suggest that in breast cancer patients, the strong anabolic effect of hyperinsulinaemia directly increases proliferation of breast tissue and breast cancer cells, resulting in stimulated DNA synthesis and proliferation, which results in a poorer prognosis.²⁰

Overweight/obesity

Obesity, which is a major determinant of insulin resistance, low-grade inflammation and endogenous sex hormone synthesis, is an established risk factor for the development of postmenopausal breast cancer.^21-23 Many studies have shown positive associations between postmenopausal weight gain and breast cancer risk. The Million Women study in the UK saw a positive association between BMI and breast cancer risk in postmenopausal women aged 50-64 years.⁹ Similarly, in a meta-analysis of 141 articles, BMI was positively associated with an increased incidence of postmenopausal breast cancer in women, along with many other cancers including colon, endometrial, oesophageal, gallbladder and pancreas.²⁴

Although the complex relationship between obesity and breast cancer is not fully understood, a key aspect is the increased production of oestrogen in excess adipose tissue in obese women after menopause.²³ Oestrogen-sensitive tissues in obese women are exposed to more oestrogen stimulation than in lean women, which can stimulate the growth and progression of breast cancer.²⁵

In addition to its ability to store lipids, adipose tissue, which is an active endocrine organ, has been shown to release a number of hormones, cytokines and factors collectively termed adipokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), leptin, adiponectin, etc, with known effects on insulin secretion and action. People with large adipose tissue stores, primarily intra-abdominal fat, produce excessive amounts of these compounds leading to a chronic state of low-level inflammation, as well as disturbed regulation of immune function and increased aromatase expression and activity – all leading to an increased risk of cancer.^26,27

Reduced levels of adiponectin are associated with obesity, and clinical studies suggest an inverse relationship between serum levels of this adipokine and the risk of developing breast cancer.²⁸ Leptin over-expression in breast cancer is associated with metastases and reduced patient survival.²⁹ Novel Irish data from Carroll et al¹⁵ showed that, in 77 patients, expression of leptin in mammary adipose tissue and ligand receptors in matched tumour tissue was significantly higher in patients with MetS compared to obese-only or normal-weight cancer patients. The components of MetS appear to disrupt this balance between leptin and adiponectin by increasing leptin and decreasing adiponectin levels. In addition, insulin and IGF-1 may play a pivotal role in mediating the potential interactions between these two adipokines and may represent an important link to tumour progression. 

Dyslipidaemia

Cholesterol has been hypothesised to increase the risk of breast cancer because cholesterol is a precursor of steroid hormones, and endogenous sex steroid hormones are positively related to breast cancer risk. Dyslipidaemia refers to a reduction in serum concentrations of HDL-C and an elevation in serum concentrations of total cholesterol, LDL cholesterol, and triacylglycerols. Postmenopausal women have higher total cholesterol, LDL cholesterol, triglycerides and lipoprotein levels.³⁰ In a prospective study examining all-cancer incidence of 1,189,719 Korean men and women, Kitahara et al³¹ reported a positive association between total cholesterol and breast cancer risk in women. Similarly, Agnoli et al⁸ discovered that serum HDL-C and serum triglycerides had the strongest association with breast cancer risk within their cohort, but concluded that all MetS components may contribute to the increased risk by multiple mechanisms.

In vitro studies have shown that low serum HDL-C stimulates the growth of hormone-dependent breast cancer cells and a low HDL-C can affect overall breast cancer risk.^5,32,33 Visceral adiposity that develops in postmenopausal women appears to be the great determinant that leads to low HDL-C. Furberg et al³³ reported that low serum HDL-C was independently associated with increased postmenopausal breast cancer risk among obese and overweight women. These findings suggest an interaction between metabolic disturbances in postmenopausal breast carcinogenesis. 

Hypertension

A few studies have shown an association between the risk of breast cancer in postmenopausal women and hypertension, although the evidence is limited.^34,35 In a population-based study, Largent et al³⁵ found that hypertension was associated with increased risk of breast cancer among 50-75-year-old women. Similarly, Agnoli et al⁸ reported that at least 36.6% of their postmenopausal cohort had hypertension and that the prevalence of hypertension increased in subjects with breast cancer versus controls.  Hypertension was independently predictive of breast cancer risk in a sample of 3,869 postmenopausal women with breast cancer as compared to 4,082 postmenopausal controls, and the association tended to increase with advancing age.⁷ Another study reported a 23% increased risk of breast cancer for hypertensive women,³⁶ however, after adjustment of confounders including BMI, the elevated risk was no longer significant. 

Conclusion

Further research should endeavour to clarify why the presence of multiple components of MetS appears to increase breast cancer risk beyond that conferred by the presence of a single component of MetS, as well as to further investigate how changes in components of metabolic syndrome, such as weight, affect incidence of disease and treatment outcomes after initial diagnosis of postmenopausal breast cancer. 

It is clear that weight gain and obesity after menopause drive the increased prevalence of MetS in postmenopausal women. Both endocrine and metabolic changes that are associated with obesity are reversible by body weight reduction. Weight loss and physical exercise are both the foundation of therapy for metabolic syndrome as they tackle the primary aetiology of the metabolic syndrome (visceral adiposity and insulin resistance). Modest weight loss of around 10% body weight can result in many physiological, psychological and metabolic benefits, including reductions of oestradiol, leptin and insulin concentrations in the sera.^37-39

Identifying MetS as a risk factor for breast cancer could justify prevention and treatment of MetS, thus helping to reduce the burden of postmenopausal breast cancer in Ireland. Given the high prevalence of MetS in postmenopausal breast cancer patients, and associated poorer prognosis and increased risk of recurrence, MetS should become part of the standard diagnostic work-up of breast cancer patients. It is clear that a prescription of diet, healthy lifestyle or other medical intervention to prevent or control the syndrome should be considered as early in life as possible.

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