Abstract
Disruption of epigenetic patterns is a major change occurring in all types of cancers. Such alterations are characterized by global DNA hypomethylation, gene-promoter hypermethylation and aberrant histone modifications, and may be modified by environment. Nutritional factors, and especially dietary lipids, have a role in the etiology of breast cancer. Thus, we aimed to analyze the influence of different high fat diets on DNA methylation and histone modifications in the rat dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. Female Sprague-Dawley rats were fed a low-fat, a high corn-oil or a high extra-virgin olive oil (EVOO) diet from weaning or from induction with DMBA. In mammary glands and tumors we analyzed global and gene specific (RASSF1A, TIMP3) DNA methylation by LUMA and bisulfite pyrosequencing assays, respectively. We also determined gene expression and enzymatic activity of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) and evaluated changes in histone modifications (H3K4me2, H3K27me3, H4K20me3 and H4K16ac) by western-blot. Our results showed variations along time in the global DNA methylation of the mammary gland displaying decreases at puberty and with aging. The olive oil-enriched diet, on the one hand, increased the levels of global DNA methylation in mammary gland and tumor, and on the other, changed histone modifications patterns. The corn oil-enriched diet increased DNA methyltransferase activity in both tissues, resulting in an increase in the promoter methylation of the tumor suppressor genes RASSF1A and TIMP3. These results suggest a differential effect of the high fat diets on epigenetic patterns with a relevant role in the neoplastic transformation, which could be one of the mechanisms of their differential promoter effect, clearly stimulating for the high corn-oil diet and with a weaker influence for the high EVOO diet, on breast cancer progression.
Highlights
Breast cancer is the most frequent malignant neoplasia among women worldwide [1]
In relation to the effect of diets, the group fed with the olive oil one (HOO) showed the highest methylation levels at all ages, close to significance compared to high corn oil (HCO) at 36 days and compared to low fat (LF) at 51 days of age (Fig 1b)
We compared the global DNA methylation between mammary gland and tumor in each experimental group at 246 days of age, finding no clear differences among tissues, except an increase in tumor compared to mammary gland in both groups fed the olive oil-enriched diet (Fig 1d)
Summary
Breast cancer is the most frequent malignant neoplasia among women worldwide [1]. In addition to genetic, epigenetic and endocrine factors, the environment, and nutritional factors, plays a key role in its etiology. Monounsaturated fatty acids (MUFA), mainly oleic acid (18:1n-9, OA), present in high quantities in olive oil, seems to be protective, some inconsistent data have been reported ranging from protective to weak stimulating effects on tumor growth [3, 4]. In this sense, abundant results have attributed a protective effect on breast cancer risk to Mediterranean Diet, characterized by the consumption of olive oil as the main source of energy [5]. The specific mechanisms by which EVOO (Extra Virgin Olive Oil) and other dietary lipids may exert their modulatory effects on cancer are not fully understood
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