Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer
ABSTRACT Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Cancer cells exposed to hyperglycemic insults acquire permanent aggressive traits of tumor growth, even after a return to euglycemic conditions. Comparative genome-wide mapping of hyperglycemia-specific open chromatin regions and concomitant mRNA expression profiling revealed that the neuregulin-1 gene, encoding an established endogenous ligand for the HER3 receptor, is activated through a putative distal enhancer. Our findings highlight the targeted inhibition of NRG1-HER3 pathways as a potential target for the treatment breast cancer patients with associated diabetes.
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- "Studies in rodents and sheep have confirmed that the availability of nutrients required for one-carbon metabolism (for example, folate, choline, methionine, and betaine, as well as selected B vitamins) at the time of conception and during pregnancy can induce epigenetically driven phenotypes in their offspring (Dolinoy et al., 2007; Sinclair et al., 2007; Waterland et al., 2006; Wolff et al., 1998). There is also evidence that changes in glucose and glucose metabolism can leave lasting epigenetic marks (Park et al., 2012; Pirola et al., 2010). Observational studies in humans are also consistent with a possible role of nutrition in epigenetics and disease. "
ABSTRACT: Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells.Cell 03/2013; 153(1):56-69. DOI:10.1016/j.cell.2013.03.004 · 33.12 Impact Factor
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ABSTRACT: Over the past several years, the field of cancer research has directed increased interest towards subsets of obesity-associated tumours, which include mammary, renal, oesophageal, gastrointestinal and reproductive cancers in both men and women. The increased risk of breast cancer that is associated with obesity has been widely reported; this has drawn much attention and as such, warrants investigation of the key mechanisms that link the obese state with cancer aetiology. For instance, the obese setting provides a unique adipose tissue microenvironment with concomitant systemic endocrine alterations that favour both tumour initiation and progression. Major metabolic differences exist within tumours that distinguish them from non-transformed healthy tissues. Importantly, considerable metabolic differences are induced by tumour cells in the stromal vascular fraction that surrounds them. The precise mechanisms that underlie the association of obesity with cancer and the accompanying metabolic changes that occur in the surrounding microenvironment remain elusive. Nonetheless, specific therapeutic agents designed for patients with obesity who develop tumours are clearly needed. This Review discusses recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment.Nature Reviews Endocrinology 06/2014; 10(8). DOI:10.1038/nrendo.2014.94 · 12.96 Impact Factor
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ABSTRACT: As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased. A number of cancers such as pancreatic, liver, breast, and female reproductive cancers have shown an increased prevalence and a higher mortality rate in diabetic patients compared to healthy subjects. Thus, this suggests an association between diabetes, especially type 2 diabetes and cancer incidence and progression. Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood. In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth. Here, we will discuss our current understanding how hyperglycemia and cancer risk may be linked, and what the implications are for the treatment of diabetic cancer patients.Diabetes & metabolism journal 10/2014; 38(5):330-6. DOI:10.4093/dmj.2014.38.5.330