Abstract
Breast cancer is the second most common cancer and a leading cause of cancer death in women. Specifically, estrogen receptor-α (ERα)-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 ERα, 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 ERα expression in ERα-negative breast cancer cells in a time-dependent manner. Chromatin immunoprecipitation analysis of the ERα promoter in each cell type revealed an increase in enrichment of acetyl-H3, acetyl-H3lysine9 (H3K9) and acetyl-H4 active chromatin markers in the ERα 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 ERα expression by resveratrol combined with pterostilbene was found to sensitize ERα-dependent response to 17β-estradiol (E2)-mediated cellular proliferation and antagonist 4-hydroxytamoxifen (4-OHT)-mediated inhibition of cellular proliferation in ERα-negative breast cancer cells. E2 and 4-OHT further affected the ERα-responsive downstream progesterone receptor (PGR) gene in ERα reactivated MDA-MB-157 cells. Collectively, our findings provide a new and safer way of restoring ERα 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.
Highlights
Breast cancer is the most frequently diagnosed cancer after skin cancer and the leading cause of cancer death among women in the United States after lung cancer [1]
Our study demonstrates that treatment of estrogen receptor (ER)-negative breast cancer cells with resveratrol and pterostilbene can reactivate estrogen receptor-α (ERα) expression through epigenetic modulation of DNA methylation and histone acetylation, H3 and H4, which result in an open chromatin structure at the ERα promoter
Densitometry analysis (Figs 1c and 2c) at 72 h was performed to display the significant increase of ERα protein expression in both of the tested Triple-negative breast cancers (TNBC) cell types
Summary
Breast cancer is the most frequently diagnosed cancer after skin cancer and the leading cause of cancer death among women in the United States after lung cancer [1]. The majority of breast cancers are ER-positive and approximately 25–30% are ER-negative, current chemotherapeutic strategies for breast cancer treatment commonly rely on the expression of important biomarkers such as estrogen receptor (ER), progesterone receptor (PGR) and HER2 protein [2,3]. It is important to recognize that in many cases the ERα gene expression in ER-negative breast cancer may not be attributed to DNA mutation, but rather acquired from epigenetic aberrations of the ERαpromoter region in ERα-negative breast cancer cells [6, 7]. Many studies have reported the possibility of converting ER status through the use of epigenetic modulating drugs such as 5-aza and/or TSA leading to the reactivation of ERα expression, which in turn sensitizes these cells to current hormone therapies. One of the limitations with this current epigenetic approach is that it often leads to adverse side effects
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