Control of Redox Homeostasis by Short-Chain Fatty Acids: Implications for the Prevention and Treatment of Breast Cancer

Abstract

Breast cancer is the leading cause of death among women worldwide, and certain subtypes are highly aggressive and drug resistant. As oxidative stress is linked to the onset and progression of cancer, new alternative therapies, based on plant-derived compounds that activate signaling pathways involved in the maintenance of cellular redox homeostasis, have received increasing interest. Among the bioactive dietary compounds considered for cancer prevention and treatment are flavonoids, such as quercetin, carotenoids, such as lycopene, polyphenols, such as resveratrol and stilbenes, and isothiocyanates, such as sulforaphane. In healthy cells, these bioactive phytochemicals exhibit antioxidant, anti-apoptotic and anti-inflammatory properties through intracellular signaling pathways and epigenetic regulation. Short-chain fatty acids (SCFAs), produced by intestinal microbiota and obtained from the diet, also exhibit anti-inflammatory and anti-proliferative properties related to their redox signaling activity-and are thus key for cell homeostasis. There is evidence supporting an antioxidant role for SCFAs, mainly butyrate, as modulators of Nrf2-Keap1 signaling involving the inhibition of histone deacetylases (HDACs) and/or Nrf2 nuclear translocation. Incorporation of SCFAs in nutritional and pharmacological interventions changes the composition of the the intestinal microbiota, which has been shown to be relevant for cancer prevention and treatment. In this review, we focused on the antioxidant properties of SCFAs and their impact on cancer development and treatment, with special emphasis on breast cancer.

Keywords: Keap1-Nrf2; antioxidants; breast cancer; butyrate; epigenetics; microbiota; redox signaling; short-chain fatty acids.

Figure 1

The demonstrated beneficial effects of the SCFA butyrate, produced by microbiota and obtained from the diet, in breast cancer cells in vitro, highlighting redox homeostasis regulation. Cdk2: cyclin-dependent kinase 2; Cdk4: cyclin-dependent kinase; 2FFAR2: free fatty acid receptor 2; FFAR3: free fatty acid receptor 3; GR109A: G-protein-coupled receptor; GSH: glutathione; HDAC: histone deacetylase; HO1: heme oxygenase 1; NO: nitric oxide; NQ1: NAD(P)H: quinone oxidoreductase-1; Nrf2: nuclear erythroid 2-related factor 2; P21: cyclin-dependent kinase inhibitor P21; H₂O₂: oxygen peroxyde; SOD: superoxide dismutase.