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.

Eicosopentaneoic Acid and Other Free Fatty Acid Receptor Agonists Inhibit Lysophosphatidic Acid- and Epidermal Growth Factor-Induced Proliferation of Human Breast Cancer Cells

“…The pathways implicated in the response include decreased Akt activation [ 5 ], increased neutral sphingomyelinase activity [ 20 ], increased BRCA levels [ 21 ], and increased PTEN levels [ 22 ]. GPCR-independent mechanisms have been reviewed [ 23 ]. To date, there is little information available concerning the roles of FFARs in breast cancer.…”

Chia (Salvia hispanica L.) flour promotes beneficial effects on adipose tissue but not on glycaemic profile of diet‐induced obesity in mice

“…In addition, studies have shown that n‐3 PUFAs can reduce monocyte chemoattractant protein‐1 (MCP‐1) levels in visceral adipose tissue, contributing to a reduction of adipose tissue inflammation in obesity. Also, n‐3 PUFA is able to inhibit NFκB activation, promoting a decrease of TNFα, IL‐1β, and IL‐6 . In another study, authors found a suppression of IL‐6 secretion in adipose cells after 48 h of treatment with the omega‐3 fatty acid docosahexaenoic acid .…”

Modulating Tumor-Associated Macrophage Polarization by Synthetic and Natural PPARγ Ligands as a Potential Target in Breast Cancer

“…In breast cancer cells, DHA strongly reduces cell viability and DNA synthesis and promotes cell death via apoptosis [9]. The proposed mechanisms include the ability of DHA to decrease the total amount of and to alter the size of lipid rafts in breast cancer cells, disrupting membrane signaling involved in the regulation of cell survival and proliferation and sensitizing cells to apoptosis [64]. The protective effects of n-3 PUFA result in reduced breast cancer incidence, growth, multiplicity and metastasis in rodent models of breast cancer [64].…”

“…The proposed mechanisms include the ability of DHA to decrease the total amount of and to alter the size of lipid rafts in breast cancer cells, disrupting membrane signaling involved in the regulation of cell survival and proliferation and sensitizing cells to apoptosis [64]. The protective effects of n-3 PUFA result in reduced breast cancer incidence, growth, multiplicity and metastasis in rodent models of breast cancer [64]. Furthermore, in a mouse model of obese postmenopausal breast cancer, n-3 PUFA supplementation reduced mammary adipose tissue inflammation and markers of inflammatory M1 macrophage infiltration [65] which were associated with reduced tumor burden, indicating that the inflammatory microenvironment promotes tumorigenesis and that n-3 PUFA directly antagonizes this process.…”