A Novel Combinatorial Epigenetic Therapy Using Resveratrol and Pterostilbene for Restoring Estrogen Receptor-alpha (ERalpha) Expression in ERalpha-Negative Breast Cancer Cells.
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Kala R, Tollefsbol TO
A Novel Combinatorial Epigenetic Therapy Using Resveratrol and Pterostilbene for Restoring Estrogen Receptor-alpha (ERalpha) Expression in ERalpha-Negative Breast Cancer Cells.
PLoS One. 2016 May 9;11(5):e0155057. doi: 10.1371/journal.pone.0155057. eCollection 2016.
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- 27159275 [ View in PubMed]
- Abstract
Breast cancer is the second most common cancer and a leading cause of cancer death in women. Specifically, estrogen receptor-alpha (ERalpha)-negative breast cancers are clinically more aggressive and normally do not respond to conventional hormone-directed therapies such as tamoxifen. Although epigenetic-based therapies such as 5-aza-2'-deoxycytidine and/or trichostatin A as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, respectively, can regulate the expression of ERalpha, this can often lead to a number of side effects. Plant-based dietary compounds such as resveratrol and pterostilbene in novel combinatorial therapy provides new avenues to target these side effects and provide similar results with a higher level of safety. Here, we report that combinatorial resveratrol and pterostilbene leads to the reactivation of ERalpha expression in ERalpha-negative breast cancer cells in a time-dependent manner. Chromatin immunoprecipitation analysis of the ERalpha promoter in each cell type revealed an increase in enrichment of acetyl-H3, acetyl-H3lysine9 (H3K9) and acetyl-H4 active chromatin markers in the ERalpha promoter region after combinatorial treatment. This treatment also resulted in a significant change in HDAC and histone acetyl transferase (HAT) enzyme activity in these cells after 3 days of treatments. The combination resulted in a significant decrease in DNMT enzyme activity and 5-methylcytosine levels in MDA-MB-157 breast cancer cells. Moreover, reactivation of ERalpha expression by resveratrol combined with pterostilbene was found to sensitize ERalpha-dependent response to 17beta-estradiol (E2)-mediated cellular proliferation and antagonist 4-hydroxytamoxifen (4-OHT)-mediated inhibition of cellular proliferation in ERalpha-negative breast cancer cells. E2 and 4-OHT further affected the ERalpha-responsive downstream progesterone receptor (PGR) gene in ERalpha reactivated MDA-MB-157 cells. Collectively, our findings provide a new and safer way of restoring ERalpha expression by regulating epigenetic mechanisms with the use of phytochemicals in combinatorial therapy. This combination can further provide effective treatment options for hormonal refractory breast cancer with available anti-hormonal therapy.