Abstract

Breast cancer is the most common cancer and the leading cause of cancer death in women. Although tamoxifen therapy is successful for some patients, it does not provide adequate benefit for those who have estrogen receptor (ER)-negative cancers. Therefore, we approached novel treatment strategies by combining two potential bioactive dietary supplements for the reactivation of ERα expression for effective treatment of ERα-negative breast cancer with tamoxifen. Bioactive dietary supplements such as green tea polyphenols (GTPs) and sulforaphane (SFN) inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), respectively, which are of central importance to cancer prevention. In the present study, we have observed that treatment of ERα-negative breast cancer cells with GTPs and SFN alone or in combination leads to the reactivation of ERα expression. The combination of 20 µg/mL GTPs and 5 µM SFN was found to be the optimal dose of ERα-reactivation at 3 days in MDA-MB-231 cells. The reactivation of ERα expression was consistently correlated with ERα promoter hypomethylation and hyperacetylation. Chromatin immunoprecipitation (ChIP) analysis of the ERα promoter revealed that GTPs and SFN altered the binding of ERα-transcriptional co-repressor complex thereby contributing to ERα-reactivation. In addition, treatment with tamoxifen in combination with GTPs and SFN significantly increased both cell death and inhibition of cellular proliferation in MDA-MB-231 cells in comparison to treatment with tamoxifen alone. Collectively, our findings suggest that a novel combination of bioactive-HDAC inhibitors with bioactive-demethylating agents is a promising strategy for the effective treatment of hormonal refractory breast cancer with available anti-estrogens.

Highlights

  • Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 23% of the total cancer cases and 14% of the cancer deaths [1]

  • These results indicate that lower doses of combined green tea polyphenols (GTPs) and SFN selectively inhibit ERanegative breast cancer cells; the optimal doses required for the transcriptional activation of ERa remained to be determined in our subsequent studies

  • EGCG, a well studied green tea polyphenol, has DNA methyltransferases (DNMTs) inhibitory activity, other catechins in GTPs such as (–)epicatechin (EC), (–)-epicatechin-3-gallate (ECG) and (–)-epigallocatechin (EGC) have been found to share similar properties they are less efficient than EGCG [13,32]

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Summary

Introduction

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 23% of the total cancer cases and 14% of the cancer deaths [1]. One of the important classifications of breast tumors is based on the presence or absence of the estrogen receptor (ER). While the majority of breast cancers are ER-positive, approximately 25–30% are ER-negative [2,3]. Patients with ER-positive breast cancer receive hormonal therapy using either selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene and lasofoxifene, or with aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestene, and have a better prognosis. Treatment of patients with ER-negative tumor is challenging due to the poor response to hormonal therapies in the absence ER expression. Alternative targeted therapies are aimed to prevent and treat hormonal refractory breast cancers

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