Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment

Abstract

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.

Fig 1.

Effects of obesity on endometrial proliferation and tumorigenesis. Obesity contributes to the increased risk of endometrial cancer in the postmenopausal uterus by a variety of mechanisms. Increased adiposity increases aromatase activity, which leads to the conversion of androgens to estrogens, to directly promote endometrial proliferation and transcription of proproliferative genes. The chronic inflammation associated with visceral adiposity is mediated by proinflammatory adipokines and leads to hyperinsulinemia, increases in insulin-like growth factor 1 (IGF1), and hyperglycemia, which fuel endometrial proliferation. A concurrent decrease in anti-inflammatory cytokines is also observed. Inflammation and an increase in estrogen metabolites further contribute to DNA damage and genetic instability. Finally, stem cells can be recruited from adipose tissue, where they contribute to a supportive tumor microenvironment. ER, estrogen receptor; IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IRS, insulin receptor substrate; mTOR, mammalian target of rapamycin. (Illustration created by Suety Kwan).