Understanding obesity and endometrial cancer risk: opportunities for prevention

Abstract

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.

Figure 1. Overview

The contribution of obesity to endometrial cancer progression and preventive strategies.

Figure 2. The systemic effects of obesity on endometrial cancer initiation and progression

Increased adiposity and inflammation coupled with the decrease in adiponectin synthesis, contribute to insulin resistance. This leads to hyperglycemia and a further compensatory increase in insulin synthesis. Hyperinsulinemia is associated with the decreased synthesis of IGF binding proteins, and increased IGF bioavailability. The simultaneous increase in estrogen production promotes additional IGF-1 synthesis. Signaling through the IGF-1R promotes endometrial proliferation with an increased risk of endometrial cancer.

Figure 3. Insulin and IGF-1 signaling drive endometrial cancer progression

The binding of IGF-1 to its receptor leads to IGF-1R autophosphorylation and the subsequent activation of multiple downstream signaling pathways. Cellular proliferation is driven through the PI3K and the MAPK pathways. Behavioral and pharmaceutical interventions, which decrease adiposity and IGF-1 levels, and that activate AMPK, and therefore represent rational therapeutic strategies for the prevention of endometrial cancer.