Phytoestrogens and prevention of breast cancer: The contentious debate

Abstract

Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed. Phytoestrogens can bind weakly to oestrogen receptors (ERs) and some have a preferential affinity for ERβ which can inhibit the transcriptional growth-promoting activity of ERα. However only saturating doses of phytoestrogens, stimulating both ERα and β, exert growth inhibitory effects. Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors (p21 and p27) and the tumour suppressor gene p53. Again these effects are only observed at high (> 10) µmol/L doses of phytoestrogens. Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes. There are, though, difficulties in reconciling epidemiological and experimental data due to the fact experimental doses, both in vivo and in vitro, far exceed the circulating concentrations of "free" unbound phytoestrogens measured in women on a high phytoestrogen diet or those taking phytoestrogen supplements.

Keywords: Breast cancer; Cell cycle; Cell signalling; Epigenomics; Phytoestrogens.

Figure 1

Multiple targets for the action of phytoestrogens.

Figure 2

Different ways in which phytoestrogens may alter gene transcription. (1) Acting as an oestrogen agonist/antagonist and the transcriptional activity of oestrogen receptors; (2) Modulating cell signalling pathways which can be activated by cell surface oestrogen receptors or growth factor receptors and ultimately activate gene transcription by activating oestrogen receptors or other transcription factors (TF); (3) Inhibiting/stimulating transcription of genes regulating apoptosis and the cell cycle; and (4) Epigenetic alterations in DNA, histone proteins and RNA to alter transcription/translation of proteins.