Oncology Department, St Thomas' Hospital, London, UK

Correspondence to: B A Stoll, Oncology Department, St Thomas' Hospital, London SE1 7EH, UK

Purpose: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined.

Mechanisms: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity.

Conclusion: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations.

International Journal of Obesity (2002) 26, 747-753. doi:10.1038/sj.ijo.0801998

abdominal obesity; adipocytes; breast cancer; hyperinsulinaemia; IGF-1; insulin resistance; oestrogen; PPAR gamma; visceral obesity

Introduction

Of six cohort studies which examined the association between breast cancer risk and upper abdominal (android) adiposity in postmenopausal women,^1,2,3,4,5,6 four have shown a positive association^1,2,3,4 as shown by waist-hip ratio (WHR) or waist circumference measurement. The association was greater than that found with either body mass index (BMI) or lower abdominal (gynoid) adiposity. It is interesting that in the two studies which failed to confirm an association in postmenopausal women,^5,6 a positive association was found in premenopausal women. In the first of these studies, it was noted (relative risk (RR) of 1.72) in the upper quartile of WHR but only in those with an elevated BMI. An intriguing additional finding in this study is that those women with lower abdominal (gynoid) adiposity and an elevated BMI showed a diminished breast cancer risk. The observation suggests that the effects of metabolic-endocrine concomitants of abdominal adiposity on breast cancer risk may be independent of those associated with an elevated BMI.

Upper abdominal adiposity is commonly associated with hyperinsulinaemic insulin resistance. A recent study of abdominal CAT scans in healthy non-obese women showed visceral fat to increase progressively after the mid-twenties, but evidence of insulin resistance was demonstrable only after the age of 60 y.⁷ Increased breast cancer risk associated with hyperinsulinaemia has been attributed to synergistic interaction between elevated free oestrogen concentrations and aberrant insulin signalling.⁸ It is relevant that multiple case-control studies, although not all, have shown a positive association between breast cancer risk and hyperinsulinaemia in postmenopausal women, although some studies are dissonant.⁹

Physiological insulin resistance is common at puberty, pregnancy or other times of increased metabolic demand. In obese females, impaired glucose tolerance may persist after puberty or after pregnancy.¹⁰ Abnormal susceptibility genes may be responsible or it may result from epigenetic effects on insulin signalling by endogenous or dietary fatty acids.¹¹ Considerable evidence suggests that breast cancer risk in women is influenced by the timing of menarche and pregnancy.¹² The association was originally ascribed to the effect of the profound hormonal changes at those times, but it is likely to be increased by certain concomitants of physiological insulin resistance triggered at the same time.⁸

Abdominal adiposity and increased breast cancer risk

A positive association has been shown between postmenopausal breast cancer risk and oestradiol concentrations in five out of six prospective studies, and in the case of testosterone concentrations in six out of six prospective studies.¹³ Both peripheral and abdominal adiposity are associated with higher endogenous oestrogen concentrations in women. Androgen production is also increased and androstenedione is aromatised to oestrone in the enlarged fat deposits.¹⁴

Imaging studies by CAT or magnetic resonance imaging (MRI) have shown increased waist measurement to reflect increased accumulation of visceral fat, although increase in abdominal subcutaneous fat is also involved.¹⁵ This so-called android fat distribution contrasts with the gynoid distribution which involves mainly the hip and gluteal regions. Sex steroid concentrations are higher in upper abdominal adiposity than in peripheral adiposity, androgen production rates being higher and its aromatisation to oestrogen greater.¹⁴ In addition, sex hormone-binding globulin (SHBG) levels are reduced by hyperinsulinaemia, more so in upper abdominal than in peripheral adiposity.¹⁶ This leads to higher concentrations of both free oestradiol and free testosterone but more particularly of the latter.

In the last decade, considerable evidence has accumulated suggesting that insulin-like growth factor 1 (IGF-1) is linked to the progression of breast cancer: (i) in the laboratory, the IGF family shows not only a mitogenic effect on breast cancer cells but also an anti-apoptotic effect;¹⁷ (ii) a cohort study and previous case-control studies have shown that higher IGF-1 concentrations in the serum are markers of increased breast cancer risk;¹⁸ (iii) synergism between IGF-1 and oestradiol has been shown in human mammary cancer cell lines;^19,20 (iv) oestradiol-stimulated growth of human breast tissue grafted into the nude mouse is associated with upregulation of the IGF-1 receptor activity.²¹

Depot-specific differences in adipocyte function

The mechanisms responsible for the association between abdominal fat accumulation and increased breast cancer risk are uncertain. The following characteristics of visceral fat accumulation have been noted. It is particularly associated with increased free fatty acid concentrations in the portal vein, altered adreno-cortical activity and androgen secretion, lowered SHBG levels, hyperinsulinaemia and hepatic gluconeogenesis. In addition, visceral adipocytes show higher catecholamine-induced lipolytic activity, decreased insulin receptor affinity and decreased leptin expression, compared to subcutaneous adipocytes.²²

Evidence noted in the previous section suggested that the increased breast cancer risk associated with visceral obesity in postmenopausal women might be related to the higher free fatty acid concentrations, higher insulin resistance, higher insulin and oestrogen concentrations and lower SHBG levels. A predominant role for visceral adipose tissue in insulin resistance is, however, not proven and it has been suggested that subcutaneous abdominal fat might be of similar, or even greater, importance.²³

Gene expression in adipocytes has been compared between visceral and subcutaneous biopsies in a group including lean and obese men and women.²⁴ It was concluded that the higher lipolytic response of visceral adipocytes may be due more to hormonal regulation of metabolic pathways than to absolute differences in enzyme production.

The higher free fatty acid concentrations in obesity are associated with greater insulin resistance,²⁵ and upper abdominal obesity shows higher insulin concentrations and greater insulin resistance than does peripheral obesity.^22,26,27 Considerable clinical and experimental evidence shows that aberrant insulin signalling and higher concentrations of insulin-like growth factor 1 (IGF-1) are associated with increased risk of several types of cancer including breast cancer.²⁸ Abnormal insulin receptor expression has been reported in visceral adipocytes and could result in aberrant signalling through the insulin receptor substrate 1 pathway.^24,29

The release of free fatty acids into the portal system depends on the balance between the adipogenic effect of insulin and the anti-adipogenic effect of growth hormone and sex steroids.³⁰ In women with visceral obesity, circulating concentrations of insulin and cortisol are increased whilst those of growth hormone and testosterone are reduced.³¹ Premenopausal women with visceral obesity show reduced serum concentrations of IGF-1, but not those with peripheral obesity.^32,33

Adipocyte differentiation is regulated through receptors of hormones and growth factors and effects are linked by intracellular signalling. In the human, androgen receptor concentrations are two-fold higher in visceral than in subcutaneous adipocytes and they modulate the effect of IGF-1 receptors on adipocyte differentiation.³⁴ Considerable evidence suggests that sex steroids are also involved in the distribution of adipose tissue.³⁵

Abdominal adiposity in women is strongly associated with increased androgen and insulin concentrations. It is however uncertain whether hyperinsulinaemia increases free testosterone concentrations by lowering SHBG levels or increases testosterone secretion by the ovary.³⁶ Both androgen and oestrogen can influence adipocyte differentiation in the rat through their own receptors, and may modulate expression of the peroxisome proliferator-activated receptor (PPAR) gamma 2 as well as IGF-1 receptor activity.³⁷

Considerable current research is focused on PPAR gamma which acts as a transcription factor for adipocyte differentiation. By controlling the final stage of differentiation, it regulates the number of adipose cells in fat depots.³⁸ PPAR gamma is activated by a wide range of fatty acid ligands but peroxisomes are specific organelles for the catabolism of very long-chain omega-3 unsaturated fatty acids.³⁹ It is reported that PPAR gamma mRNA expression in visceral fat is lower than that in subcutaneous fat in lean subjects but not in obese subjects.²⁴

The role of PPAR gamma in adipocyte differentiation is however still unclear because of evidence of fatty acid binding by PPAR gamma 1, 2 and 3 isoforms, and a possible role for PPAR delta (previously designated beta). Increased frequency of the Pro 12 Ala polymorphism in the PPAR gamma gene has been reported in severely overweight patients.^40,41 Large subsequent studies have failed to show this correlation in morbidly obese individuals or type 2 diabetes cases.^42,43

Leptin is thought to have a role in the accumulation of visceral fat, and insulin resistance is associated with elevated plasma leptin concentrations.³⁰ This observation may be related to the reduction of leptin expression in visceral adipocytes compared to subcutaneous adipocytes.⁴⁴ Leptin concentrations are positively correlated with subcutaneous abdominal obesity but not with the waist-hip circumference ratio.⁴⁵ Leptin activity is also positively associated with adipocyte size, and women show both higher leptin concentrations and more hypertrophy of adipocytes.⁴⁶ It may be relevant that PPAR gamma also participates in regulating the size of mature adipocytes.⁴⁷

Western lifestyle and breast cancer risk markers

The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain some clinical associations between breast cancer risk and age at menarche, pregnancy or at onset of obesity. Breast cancer is about five times more common in Western women than in Japanese women, yet the breast cancer risk among Japanese migrants to Hawaii or the USA approaches that of their neighbours within a couple of generations.⁴⁸ Certain aspects of the Western lifestyle are thought to be involved, particularly overweight and obesity.

In Western populations, the mean age at the onset of menarche has fallen from 16 to 13 y during the twentieth century and practically all studies agree that onset of menarche by the age of 13 y is associated with increased breast cancer risk.⁴⁹ Menarche is likely to be triggered by a threshold level of fatness⁵⁰ and rich nutrition in childhood together with inadequate physical activity are linked to earlier onset of menarche.

Childhood obesity also is associated with menarche at an early age,⁵¹ especially in the case of abdominal obesity.⁵² Girls with an earlier menarche tend to be more obese as young adults. Obesity in teenage tends to continue into adult life⁵³ and about one-third of obese adult women report that they were obese in adolescence.⁵⁴ Of considerable importance is evidence that continuation of obesity after adolescence is associated with increased risk of insulin resistance in adult life.⁵⁵

The greater height and weight for age which is associated with earlier menarche in Western girls is usually associated with earlier onset of physiological insulin resistance. It is accompanied by raised IGF-1 concentrations and leads to an earlier growth spurt at the time of puberty.⁵⁶ Multiple studies have reported an association between adult tallness and breast cancer risk both in pre- and postmenopausal women.⁵⁷

Some clinical risk factors reported in the relationship of pregnancy to breast cancer risk may relate to the persistence of adiposity and insulin resistance after pregnancy. Numerous studies show that full-term pregnancy before the age of 25 y diminishes breast cancer risk and this is presumed to result from differentiation changes in the mammary epithelium. However, first childbirth occurring after the age of 35 y is associated with greater breast cancer risk than is nulliparity.⁵⁸ Even second or later childbirths after the age of 35 y may increase breast cancer risk.^59,60

These observations may be linked to studies which report that breast cancer risk is increased for a period of 3 y after a woman's last full-term birth.^61,62 Weight gained during pregnancy is a major contributor to subsequent obesity, and a study of 2788 pregnancies showed persistence of weight gain averaging 2-3 kg and an increased risk of abdominal obesity independently of weight gain.⁶³ Another study has reported increased risk of abdominal obesity in middle-aged women to be positively related to the number of live births.⁶⁴

During pregnancy most women accumulate subcutaneous fat which contributes to their overall weight gain, and late pregnancy is associated with the development of insulin resistance both to glucose metabolism⁶⁵ and to lipid metabolism.⁶⁶ These metabolic changes usually disappear post partum, but this may not apply in the case of women whose BMI is high early in their pregnancy.⁶⁷ It is reported that women who are obese at 13 weeks gestation retain more of their pregnancy weight-gain post partum and show more abdominal localisation of fat than do women who were not obese early in pregnancy.

An anomalous feature in Western women is the contrasting effect of obesity on breast cancer risk in pre- and postmenopausal women. A significantly increased breast cancer risk in obese postmenopausal women is reported in the majority of published studies, but a modestly decreased risk in obese premenopausal women.⁶⁸ It has been stressed that this paradoxical association is found in high-risk Western populations but not in populations at low risk to breast cancer.⁶⁹ When studies on the effect of obesity on breast cancer risk are stratified according to the age when obesity manifested, they show that only obesity which appears before 18 y is clearly associated with a protective effect against premenopausal breast cancer.⁷⁰ Moreover, it is not clearly associated with protection against postmenopausal breast cancer. Obesity manifesting after teenage is associated with a higher risk of postmenopausal breast cancer in most studies, and this has been confirmed in a recent cohort study.⁷¹

It is necessary to explain the reduced risk of premenopausal breast cancer in Western women associated with obesity before the age of 18 y. It could lead to a higher incidence of anovulatory cycles⁷⁰ and increase in androgen/oestrogen blood concentration in teenage girls,⁷² due to the effect of obesity-related hyperinsulinaemia on ovarian steroidogenesis. In Asian populations with a low breast cancer risk, teenage obesity is relatively uncommon and unlikely to be associated with a protective effect against premenopausal breast cancer.⁷⁰

Pathogenesis of hyperinsulinaemic insulin resistance

Although usually associated, it is still uncertain whether accumulation of abdominal visceral adipose tissue has a causal role in the development of insulin resistance.⁷³ Weight loss in obese subjects is reported to reduce visceral fat deposits more than peripheral fat deposits.²⁷ It has a greater effect in reducing insulin resistance, insulin and noradrenaline concentrations and in increasing catecholamine stimulation of lipolysis in visceral than in peripheral obesity.²² These observations support the view that most of the metabolic changes associated with abdominal obesity are a consequence rather than a cause of the accumulation of visceral adipose tissue.²²

Familial clustering of abdominal visceral obesity is reported⁷⁴ and a study of 119 twin pairs of postmenopausal women suggests that aberrant genes responsible for abdominal obesity may differ from those involved in peripheral obesity.⁷⁵ Although predisposition to abdominal obesity may be genetically determined, it is likely to be triggered by epigenetic lifestyle factors affecting expression of genes influencing fat and glucose metabolism.⁷⁶ Most commonly proposed are gene mutations in the insulin receptor, insulin receptor substrate, beta 3 adrenergic receptor and PPAR gamma.^76,77

In Western populations, abdominal fat begins to accumulate in childhood and adolescence and is associated with insulin resistance.⁷⁸ Whilst abdominal fat accumulation tends to be visceral in obese children, it usually involves subcutaneous fat in lean children.⁷⁸ As noted in a previous section, androgen receptor activity in adipocytes is related to that of IGF-1 receptor, and the changing sex steroid environment during puberty may contribute to variations in fat distribution.³⁰ The insulin-resistant state associated with abdominal obesity may thus be regarded as a continuum or shifting progression of glucose intolerance which may terminate in type 2 diabetes when hyperglycaemia prevails.

Both increasing age and obesity increase the prevalence of insulin resistance, but it is rarely diagnosed early in its evolution. One study in the USA found it in 44% of non-obese healthy postmenopausal women,⁷⁹ and as many as 25% of Western populations are reported to show fasting hyperinsulinaemia. Visceral obesity is common in individuals developing type 2 diabetes and this is now the predominant type of diabetes in Western populations. Recent cohort and case-control studies report a positive association between diabetes mellitus and increased breast cancer risk.^80,81 Earlier studies failed to show such association,^82,83 probably because they were mainly based on an association with type 1 diabetes in a younger population.⁸⁴ In this group, menstrual irregularity is common⁸⁵ and is associated with anovulation, which can reduce breast cancer risk.⁷⁰

Considerable evidence suggests that visceral obesity is also important in the development of the metabolic syndrome. Its major components are abdominal obesity, hyperinsulinaemia, glucose intolerance, dyslipidaemia, atherosclerosis and hypertension. The incidence of the syndrome varies widely between races and family groups, and some non-Caucasian groups are particularly susceptible to its development, the risk becoming higher when their lifestyle becomes Westernised. The increasing prevalence of breast cancer in Western women parallels that of visceral obesity and insulin resistance. It has been postulated that epigenetic, environmental and lifestyle factors which promote mammary carcinogenesis may be similar to those favouring insulin resistance. Both breast cancer and visceral obesity are likely to be polygenic and multifactorial in their causation but may share some metabolic-endocrine manifestations.

Conclusion

It has been shown that long continued insulin resistance associated with upper abdominal adiposity can lead to aberrant insulin signalling through the insulin receptor 1 pathway in the cell. Multiple studies confirm that the expression of oestrogen receptor (ER) and that of the insulin-like growth factor 1 receptor (IGF-1R) are positively correlated in breast cancer specimens.⁸⁶ The function of the two receptors is strongly interlinked in enhancing proliferative activity in normal and malignant human mammary epithelial cells in culture (reviewed in Stoll⁸⁷). Together, the evidence may point to a mechanism by which upper abdominal obesity and associated insulin resistance may increase the risk of breast cancer in women. Evidence that visceral fat accumulation relates predominantly to insulin resistance after the age of 60 y⁷ may explain why upper abdominal obesity is more strongly related to increased breast cancer risk in postmenopausal than in premenopausal women. The previous section has discussed the relevance of these observations to the high risk of postmenopausal breast cancer in industrialised Western populations.

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