Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and Biology

Abstract

Once considered a problem of Western nations, obesity (body mass index ≥30 kg/m²) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. During the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States, African American women are more likely than non-Hispanic European American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study found that obesity (increased waist/hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African American women. To date, the data are complex and sometimes contradictory. We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology.

Figure 1

Relative circulating insulin and glucose levels in a healthy individual (A), an insulin-resistant individual (B), and an individual with diabetes (C). Insulin resistance (prediabetes) occurs when the body demands increasingly greater amounts of insulin to deliver glucose to the muscle and other organs. When individuals with insulin resistance eat, insulin may increase to 5- to 10-fold higher than in individuals without insulin resistance. HbA_1c, hemoglobin A_1c.

Figure 2

Insulin resistance promotes weight gain and tissue inflammation. After eating, serum glucose levels increase and trigger the release of the hormone insulin. Normally, this increase in serum insulin promotes glucose uptake into the peripheral tissue. Muscle tissue is the primary user of glucose and a major regulator of insulin sensitivity. In an individual who is insulin resistant, the peripheral tissue progressively loses its ability to transport glucose, leading to an increase in serum glucose. In response to this increased level of serum glucose, β-cells in the pancreas increase production of insulin. Insulin promotes hunger and, as a result, insulin-resistant individuals become hungrier (not full) after eating, leading to a positive feedback cycle of progressively increasing weight gain, insulin resistance, and adipose tissue inflammation. Ultimately, the β-cells of the pancreas are unable to keep up with demand and diabetes (pancreas failure) ensues.

Figure 3

A: Metabolically normal, lean adipose tissue produces anti-inflammatory cytokines and is associated with CD4⁺ T cells and M2 macrophages. B: As obesity increases, adipocytes undergo hypertrophy, begin to produce proinflammatory cytokines, and are associated with CD8⁺ T cells and M1 macrophages. C: Finally, as metabolic dysfunction worsens, adipose tissue produces only proinflammatory cytokines, and crown-like structures of necrotic adipocytes surrounded by M1 macrophages appear. CCL2, chemokine (C-C motif) ligand 2; IFN-γ, interferon-γ; IL, interleukin; TNBC, triple-negative breast cancer.