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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 ER\u03b1-positive breast cancer cells. However, the role of GE in ER\u03b1-negative breast cancer remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We have evaluated the\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      epigenetic effects of GE on\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      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\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that GE can reactivate\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ER\u03b1-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ER\u03b1-dependent cellular responses to activator 17\u03b2-estradiol (E\n                      <jats:sub>2<\/jats:sub>\n                      ) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      promoter thereby contributing to\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ER\u03b1-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      reactivation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our studies suggest that soybean genistein can epigenetically restore\n                      <jats:italic>ER\u03b1<\/jats:italic>\n                      expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ER\u03b1-negative breast cancer which will provide more effective options in breast cancer therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/1476-4598-12-9","type":"journal-article","created":{"date-parts":[[2013,2,4]],"date-time":"2013-02-04T11:16:58Z","timestamp":1359976618000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":171,"title":["Epigenetic reactivation of estrogen receptor-\u03b1 (ER\u03b1) by genistein enhances hormonal therapy sensitivity in ER\u03b1-negative breast cancer"],"prefix":"10.1186","volume":"12","author":[{"given":"Yuanyuan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed M","family":"Meeran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta N","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabitha M","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trygve O","family":"Tollefsbol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,2,4]]},"reference":[{"key":"1081_CR1","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/35021093","volume":"406","author":"CM Perou","year":"2000","unstructured":"Perou CM, S\u00f8rlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, L\u00f8nning PE, B\u00f8rresen-Dale AL, Brown PO, Botstein D: Molecular portraits of human breast tumours. 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