The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer

Abstract

Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index-defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin.

Keywords: breast cancer; inflammation; insulin.

Figure 1

Stimulation of breast cancer cell proliferation and invasion by insulin. Enhanced adipose stromal cell estrogen production and suppression of hepatic SHBG synthesis with elevated estrogen bioactivity stimulate ER-positive cells indirectly by a combination of endocrine and paracrine activities, and insulin action on insulin receptor-expressing cells promotes both ER-positive and ER-negative breast cancer progression. Abbreviations: A2, androstenedione; E1, estrone; E2, estradiol; HSD, 17β-hydroxysteroid dehydrogenase; SHBG, sex hormone-binding globulin.

Figure 2

Inflammation and breast cancer: the paracrine interactions of adipose stromal cells and M1 macrophages with breast cancer epithelial cells, and promotion of tumor-related angiogenesis by stromal cell and M2 macrophage-secreted angiogenic factors. * A partial phenotypic shift in favor of M2 macrophages, VEGF production, and angiogenesis may occur later in the course of tumorigenesis. Abbreviations: ER, estrogen receptor; TNF-α, tumor necrosis factor-α; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; PGE2, prostaglandin E2; VEGF, vascular endothelial growth factor; MMPs, matrix metalloproteinases.