Breast cancer (BC) is the most common cancer and second leading cause of cancer mortality in women worldwide. Validated biomarkers enhance efforts for early detection and treatment, which reduce the risk of mortality. Epigenetic signatures have been suggested as good biomarkers for early detection, prognosis and targeted therapy of BC. Here, we highlight studies documenting the modifying effects of dietary fatty acids and obesity on BC biomarkers associated with DNA methylation. We focus our analysis on changes elicited in writers of DNA methylation (i.e., DNA methyltransferases), global DNA methylation and gene‐specific DNA methylation. To provide context, we precede this discussion with a review of the available evidence for an association between BC incidence and both dietary fat consumption and obesity. We also include a review of well‐vetted BC biomarkers related to cytosine‐guanine dinucleotides methylation and how they influence BC risk, prognosis, tumour characteristics and response to treatment. Linked Articles This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10–16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.

A diet high in n-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by n-6 fatty acids of enterohepatic bile acid (BA) metabolism. The farnesoid X receptor (FXR) is a nuclear receptor that regulates BA homeostasis in the liver and intestine. This study aims to compare the effects on FXR regulation and BA metabolism of a palm oil-based diet providing 28% energy (28%E) from fat and low n-6 linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and high (28%E) in LA (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxrα1 isoform under the control of the intestine-specific Villin promoter (Fxrα1TG) were fed the CNTL or n-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the n-6HFD supports higher weight gain in both WT and FxrαTG littermates; increases the expression of Fxrα1/2, and peroxisome proliferator-activated receptor-γ1 (Pparγ1) in the small intestine, Fxrα1/2 in the colon, and cytochrome P4507A1 (Cyp7a1) and small heterodimer protein (Shp) in the liver; and augments the levels of total BA in the liver, and primary chenodeoxycholic (CDCA), cholic (CA), and β-muricholic (βMCA) acid in the cecum. Intestinal overexpression of the Fxra1TG augments expression of Shp and ileal bile acid-binding protein (Ibabp) in the small intestine and Ibabp in the proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Pparγ in the small intestine. We conclude that intestinal Fxrα1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of human-specific primary bile acids in the cecum.

Objectives The farnesoid-X-receptor (FXR) regulates bile acid (BA) homeostasis, protecting against colonic inflammation and cancer. Conversely, increased intestinal levels of BA and expression of cyclooxygenase-2 (COX-2) increase the risk of inflammation and cancer of the colon. Earlier studies from our laboratory show that a diet rich in n-6 linoleic acid (n-6HFD) epigenetically activates Fxr, inducing the expression of downstream factors that regulate BA homeostasis. However, the chronic exposure to n-6HFD induces COX-2 expression through CpG demethylation of the PTSG-2 gene and activates the β-catenin pathway. The objective of this study is to determine in a mouse and cell culture models the influence of an n-6HFD on endpoints of intestinal inflammation and the modifying effects of overexpression of FXR. Methods A mouse line overexpressing FXR in the intestine was developed by injecting an FXRtransgene (FxrTG) construct driven by the villin promoter into FVB zygotes, and then crossed with C57BL6 mice. The small intestine and colon tissue were collected from male founders. Changes in gene expression and DNA methylation were measured by real-time PCR (RT-PCR). Cell culture experiments were performed in colonic human fetal cell (FHC) cells treated with linoleic acid (LA). Results Expression analyses by RT-PCR reveal increased expression of FxrTG in distal small intestine and proximal and distal colon. These changes are paralleled by accumulation of ileal bile acid-binding protein (IBABP) and small heterodimer partner (SHP), two downstream targets of FXR, and a reduction in expression of COX-2. Western blot of colon FHC shows LA induces expression of COX-2. Conclusions We conclude that increased expression of FXR triggers the expression of genes involved in BA homeostasis and downregulates genes involved in inflammation. The FxrTG mouse model is being used to investigate the modifying effects of diets varying in fatty acid level and profile on endpoints of intestinal inflammation and cancer. Funding Sources This work was supported by a grant from NIFA, GRANT12445471, and a predoctoral training grant to M.G.D. from the Cancer Biology Training Grant T32CA009213.