Abstract
Conventional cancer prevention has primarily focused on single chemopreventive compounds that may not be sufficiently efficacious. We sought to investigate potential combinatorial effects of epigenetic bioactive botanicals including epigallocatechin-3-gallate (EGCG) in green tea polyphenols (GTPs) and sulforaphane (SFN) in broccoli sprouts (BSp) on neutralizing epigenetic aberrations in estrogen receptor-α (ERα) leading to enhanced anti-hormone therapeutic efficacy in ERα-negative breast cancer. Our results showed that this combinatorial treatment re-sensitized ERα-dependent cellular inhibitory responses to an estrogen antagonist, tamoxifen (TAM), via at least in part, epigenetic reactivation of ERα expression in ERα-negative breast cancer cells. Further in vivo studies revealed the combinatorial diets of GTPs and BSp significantly inhibited breast tumor growth in ERα-negative mouse xenografts, especially when combined with TAM treatment. This novel treatment regimen can lead to remodeling of the chromatin structure by histone modifications and recruitment changes of transcriptional factor complex in the ERα promoter thereby contributing to ERα reactivation and re-sensitized chemotherapeutic efficacy of anti-hormone therapy. Our studies indicate that combinatorial bioactive botanicals from GTPs and BSp are highly effective in inhibiting ERα-negative breast cancer due at least in part to epigenetic reactivation of ERα, which in turn increases TAM-dependent anti-estrogen chemosensitivity in vitro and in vivo.
Highlights
The progressive loss of balance between environmental impacts and endogenous regulations in genetic/epigenetic blueprints is the primary contributor for major human pathologies such as cancers[1, 2]
To elucidate the combinatorial efficacy of the green tea polyphenol EGCG and broccoli sprouts SFN, we initiated our study to determine the optimal dose of combined EGCG and SFN treatment that will induce synergistic cellular growth inhibition in estrogen receptor-α (ERα)-negative breast cancer MDA-MB-231 and MDA-MB-157 cells (Fig. S1)
Our results showed that EGCG or SFN treatment alone or in combination resulted in significant ERα transcriptional activation (p < 0.001) in both ERα-negative breast cancer cells such as MDA-MB-231 cells (Fig. 2A) and MDA-MB-157 (Fig. 2B), but combination treatment induced a synergistic effect of ERα reactivation compared to the individual treatment of EGCG or SFN, especially in MDA-MB-231 cells
Summary
The progressive loss of balance between environmental impacts and endogenous regulations in genetic/epigenetic blueprints is the primary contributor for major human pathologies such as cancers[1, 2]. Recent studies demonstrate that a small portion of bioactive diets as referred to “epigenetic diets” may act as environmental regulators that shape the activity of the epigenomic profile by www.nature.com/scientificreports/ Among these epigenetic dietary components, we are interested in EGCG in green tea polyphenols and SFN in broccoli sprouts due to their potent anti-cancer properties and robust roles in influencing epigenetic regulation. Studies have shown that green tea polyphenol EGCG imparts its anticancer effects through various mechanisms including the induction of cell cycle arrest and apoptosis as well as inhibition of tumor metastasis and angiogenesis[14, 15] Another mechanism of EGCG pertains to epigenetic regulation via inhibition of an important epigenetic modulator, DNA methyltransferase (DNMT), leading to correction of excessive hypermethylation in cancer cells[16]. This study will facilitate more effective uses of combinatorial epigenetic dietary approaches to refractory ERα-negative breast cancer, which will provide more effective options in breast cancer prevention and therapy
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