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Author (up) Li, Y.; Meeran, S.M.; Patel, S.N.; Chen, H.; Hardy, T.M.; Tollefsbol, T.O. url  doi
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  Title Epigenetic reactivation of estrogen receptor-alpha (ERalpha) by genistein enhances hormonal therapy sensitivity in ERalpha-negative breast cancer Type Journal Article
  Year 2013 Publication Molecular Cancer Abbreviated Journal Mol Cancer  
  Volume 12 Issue 1 Pages 9  
  Keywords  
  Abstract ABSTRACT: BACKGROUND: Estrogen receptor-alpha (ERalpha)-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ERalpha-positive breast cancer cells. However, the role of GE in ERalpha-negative breast cancer remains unknown. METHODS: We have evaluated the in vitro and in vivo epigenetic effects of GE on ERalpha reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR) assay, western-blot assay, immunoprecipitation (ChIP) assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo. RESULTS: We found that GE can reactivate ERalpha expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERalpha-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERalpha-dependent cellular responses to activator 17beta-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERalpha promoter thereby contributing to ERalpha reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERalpha-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERalpha reactivation. CONCLUSIONS: Our studies suggest that soybean genistein can epigenetically restore ERalpha expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ERalpha-negative breast cancer which will provide more effective options in breast cancer therapy.  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1476-4598 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23379261 Approved no  
  Call Number @ @ Serial 37699  
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