Phytoestrogens and prevention of breast cancer: The contentious debate


Over the last decade there has been an explosion in the number of studies concerning epigenetic changes and the development and progression of breast cancer[61] and not surprisingly these have included studies on the ability of phytoestrogens to alter the epigenome which could be useful in the prevention of cancer[61-63]. In fact studies have indicated that early childhood exposure to phytoestrogens could protect against breast cancer in later life[62] and references therein and this could involve epigenetic events (Figure ​(Figure2).2). Epigenetic changes are defined as heritable changes in gene expression which do not involve mutations of DNA nucleotide sequences. They include DNA methylation, histone acetylation and microRNA’s (miRNAs).

DNA methylation occurs on cytosine in the cytosine-phosphate-guanine (CpG) dinucleotide sequence of genomic DNA, a reaction catalysed by DNA methyl transferases (DNMTs). CpG dinucleotide rich regions (known as CpG islands) are found in the promoter region of approximately 60% of all human genes and, whilst most CpG islands are unmethylated in normal cells, they become hypermethylated in cancerous cells leading to gene suppression, including the tumour-suppressing genes[61]. Along with DNMTs are the methyl-CpG-binding domain family of proteins which bind to a methylated gene and can inhibit transcriptional activity by altering chromatin structure. Chromatin structure can also be modified by histone acetylation which is catalysed by histone acetylase (HAT) and results in a more open structure of chromatin allowing access for transcription factors to DNA. The reverse occurs when histone proteins become deacetylated and this reaction is catalysed by histone deacetylases (HDACs). Histones may also be methylated by histone methyl transferases (HMT’s) and generally methylation causes gene transcription to be switched off. The most recent participant of the epigenetic field are the miRNAs, small non-coding RNAs that inhibit protein expression of target genes by binding to the 3’-untranslated region of mRNA causing degradation or inhibition of mRNA of the target gene[61,62] and references therein.

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The most widely studied dietary components in relation to epigenetic changes are the tea polyphenols, epicatechins and epigallocatechins (EGCCs), the isoflavones, genistein and diadzein, resveratrol and curcumin and all have been well reviewed recently[63-66]. Relatively few studies have been directed towards epigenetic changes in breast cancer models and results have been inconclusive[61,62].

Recent studies have shown that 20-40 µmol/L genistein stimulated expression of the tumour suppressing genes, p21WAF1 and p16INK4a, in breast cancer cells and that this was associated with a small reduction in the activity of HDACs but a large increase in the activity of HMTs[67]. The same group also showed that genistein can reactivate ERα expression in ER-ve breast cancer cells and that this effect was associated with increased markers of histone acetylation in the ERα promoter region and decreased activity of HDAC and DNMT[68]. Another study showed that µmol/L doses of genistein and diadzein “might reverse” DNA hypermethylation in breast cancer cells thus restoring expression of the oncosuppressor genes BRCA1 and BRCA2[69]. In biopsies of human breast tissue specific DNMT transcripts were increased in cells taken from the tumourous tissue compared to adjacent normal breast tissue and parallel studies showed that treatment of breast cancer cells lines with genistein, resveratrol, curcumin and EGCC also reduced the mRNA of the same DNMTs[70]. Whilst all these studies have been performed acutely with high doses of single phytoestrogens, we showed that long-term treatment with 10 nmol/L genistein down-regulated the expression of acetylated histone3, cyclin D1 and procaspase 9 and reduced the growth promoting effects of E2 and epidermal growth factor[71].

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It is clear that both nutrition and exposure to phytoestrogens and other phytochemicals can have dramatic effects on epigenetic events and that these may become heritable through transgenerational mechanisms. Thus their impact on both disease and the health of future generations needs to be carefully considered.


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About the Author: Tung Chi