Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown.

Background: The status of estrogen receptor-α (ERα) is critical to the clinical prognosis and therapeutic approach in breast cancer. ERα-negative breast cancer is clinically aggressive and has a poor prognosis because of the lack of hormone target-directed therapies. Previous studies have shown that epigenetic regulation plays a major role in ERα silencing in human breast cancer cells. Dietary green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), is believed to be an anticancer agent in part through its regulation of epigenetic processes. Results: In our current studies, we found that EGCG can reactivate ERα expression in ERα-negative MDA-MB-231 breast cancer cells. Combination studies using EGCG with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), revealed a synergistic effect of reactivation of ERα expression in ERα-negative breast cancer cells. Reactivation of ERα expression by EGCG and TSA treatment was found to sensitize ERα-dependent cellular responses to activator 17β-estradiol (E₂) and antagonist tamoxifen in ERα-negative breast cancer cells. We also found that EGCG can lead to remodeling of the chromatin structure of the ERα promoter by altering histone acetylation and methylation status thereby resulting in ERα reactivation. A decreased binding of the transcription repressor complex, Rb/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, in the regulatory region of the ERα promoter also contributes to ERα transcriptional activation through treatment with EGCG and/or TSA. Conclusions: Collectively, these studies show that green tea EGCG can restore ERα expression by regulating epigenetic mechanisms, and this effect is enhanced when combined with an HDAC inhibitor. This study will facilitate more effective uses of combination approaches in breast cancer therapy and will help to explore more effective chemotherapeutic strategies toward hormone-resistant breast cancer.

The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases.

Nutrition is the most important environmental factor that can influence early developmental processes through regulation of epigenetic mechanisms during pregnancy and neonatal periods. Maternal diets or nutritional compositions contribute to the establishment of the epigenetic profiles in the fetus that have a profound impact on individual susceptibility to certain diseases or disorders in the offspring later in life. Obesity is considered a global epidemic that impairs human life quality and also increases risk of development of many human diseases such as diabetes and cardiovascular diseases. Studies have shown that maternal nutrition status is closely associated with obesity in progenies indicating obesity has a developmental origin. Maternal diets may also impact the early establishment of the fetal and neonatal microbiome leading to specific epigenetic signatures that may potentially predispose to the development of late-life obesity. This article will review the association of different maternal dietary statuses including essential nutritional quantity and specific dietary components with gut microbiome in determining epigenetic impacts on offspring susceptibility to obesity.

It is thought that germ cells and preimplantation embryos during development are most susceptible to endogenous and exogenous environmental factors because the epigenome in those cells is undergoing dramatic elimination and reconstruction. Exposure to environmental factors such as nutrition, climate, stress, pathogens, toxins, and even social behavior during gametogenesis and early embryogenesis has been shown to influence disease susceptibility in the offspring. Early-life epigenetic modifications, which determine the expression of genetic information stored in the genome, are viewed as one of the general mechanisms linking prenatal exposure and phenotypic changes later in life. From atmospheric pollution, endocrine-disrupting chemicals to heavy metals, research increasingly suggests that environmental pollutions have already produced significant consequences on human health. Moreover, mounting evidence now links such pollution to relevant modification in the epigenome. The epigenetics diet, referring to a class of bioactive dietary compounds such as isothiocyanates in broccoli, genistein in soybean, resveratrol in grape, epigallocatechin-3-gallate in green tea, and ascorbic acid in fruits, has been shown to modify the epigenome leading to beneficial health outcomes. This review will primarily focus on the causes and consequences of prenatal environment pollution exposure on the epigenome, and the potential protective role of the epigenetics diet, which could play a central role in neutralizing epigenomic aberrations against environmental pollutions.