Review
Oncology
Understanding obesity and endometrial cancer risk: opportunities for prevention

https://doi.org/10.1016/j.ajog.2011.05.042Get rights and content

Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.

Section snippets

Obesity and hormone imbalance

Estrogen is a known endometrial growth factor. Although the ovaries are the primary source of estrogen in premenopausal women, peripheral tissues, which include adipose tissue, become the primary sources of circulating estrogen in postmenopausal women.7, 8, 9 Androgens are converted to estrone and estradiol by the enzyme aromatase in adipose tissue. Aromatase is produced by mesenchymal stromal cells, which include adipocyte stem cells, and to a lesser degree by mature adipocytes themselves.

Type 2 diabetes mellitus and hyperinsulinemia

Hyperinsulinemia and the insulin-resistant state are associated closely with obesity. Epidemiologically, a number of studies have shown a modest association of diabetes mellitus with endometrial cancer risk.24, 25, 26, 27, 28 Interestingly, in 3 studies the most significant risks were seen in women who were both obese and diabetic.24, 27, 29 A study by Troisi et al30 examined insulin levels in women with endometrial cancer compared with control subjects to determine whether elevated insulin

IGF

Systemic levels of IGFs are also altered by obesity. Six IGF-binding proteins (IGFBPs) bind to and modulate IGF bioactivity by interfering with receptor binding. Although increased estrogen production directly increases IGF-1 synthesis,36, 37 sustained hyperinsulinemia results in the decreased synthesis of IGFBP1 and 2.7 IGFBP1 is most highly expressed by human endometrium.38, 39 Therefore, obesity contributes to the simultaneous increase in circulating IGF and decrease in IGFBP1 and results in

Insulin and IGF signaling pathways

Insulin and IGFs use common signaling mechanisms.42 As illustrated in Figure 3, on ligand binding, receptor-mediated phosphorylation of the insulin receptor substrate 1 (IRS-1) scaffold protein results in the activation of both the phosphoinositide kinase 3 (PI3K)/AKT/mammalian target of rapamycin (mTOR) and MAPK signaling pathways, which promote cell survival and proliferation.42

Hyperactivity of the PI3K/AKT/mTOR pathway is observed frequently in endometrial cancer. The ubiquitously expressed

Adipokines

Adipose tissue is a complex endocrine organ that secretes a variety of both anti- and proinflammatory factors classified as “adipokines.” The state of chronic systemic inflammation that is associated with obesity is linked increasingly to the development of insulin resistance and chronic hyperinsulinemia.43, 44, 45, 46, 47, 48, 49, 50, 51, 52 For example, secretion of the adipokine, tumor necrosis factor alpha (TNFα), disrupts insulin receptor signaling by inducing the inhibitory

Rational interventions

These known biochemical mechanisms by which overweight and obesity contribute to endometrial cancer risk suggest several rational strategies for cancer prevention. These include behavioral, pharmaceutical, and surgical interventions that prevent or reverse the hormonal and metabolic imbalances associated with obesity and insulin resistance.

Comment

Current evidence suggests that, by targeting the hormonal imbalances and hyperactive proliferative pathways associated with obesity, the lifetime risk of endometrial cancer can be reduced significantly. Although achieving and maintaining a healthy bodyweight by diet and exercise represents the ideal solution to endometrial cancer prevention, the reality of the worldwide obesity epidemic necessitates the availability of pharmaceutical and surgical alternatives to reduce the impact of obesity on

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