n-3 polyunsaturated fatty acids and mechanisms to mitigate inflammatory paracrine signaling in obesity-associated breast cancer

Abstract

Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

Figure 1

Summary of inflammatory mediator paracrine interactions produced within the obese mammary tissue tumor microenvironment highlighting the complex interactions mediated by adipocytes, macrophages and epithelial cells (main cellular sources of inflammatory mediators). Solid arrows denote stimulatory effects and dotted arrows denote inhibitory effects between inflammatory mediators. Red arrows indicate the effects of n-3 PUFA to increase or decrease inflammatory mediator levels, thereby subsequently up-regulating (adiponectin, n-3 PUFA-derived eicosanoids) or down-regulating (leptin, n-6 PUFA-derived eicosanoids, cytokines (TNFα, IL-1β, IL-6 and MCP-1) and macrophage tissue infiltration). TAM, tumor associated-macrophage; CLS, crown-like structure; HIF-1α, hypoxia induced factor-1α; COX-2, cyclooxygenase-2; PGE₂, prostaglandin E₂; TNFα, tumor necrosis factor-α; IL, interleukin; MCP-1, monocyte chemoattractant protein-1.