Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer.
Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer.
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DOI：
10.1186/1476-4598-12-9
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发表时间：
2013-02-04
期刊：
影响因子：
37.3
通讯作者：
Tollefsbol TO
中科院分区：
文献类型：
--
作者：
Li Y;Meeran SM;Patel SN;Chen H;Hardy TM;Tollefsbol TO
雌激素受体α（ERα）阴性乳腺癌在临床上具有侵袭性，通常对传统雌激素靶向治疗没有反应。大豆异黄酮金雀异黄酮 (GE) 已被证明可以预防和抑制乳腺癌，最近的研究表明，GE 可以增强雌激素拮抗剂他莫昔芬 (TAM) 的抗癌能力，特别是在 ERα 阳性乳腺癌细胞中。然而，GE 在 ERα 阴性乳腺癌中的作用仍不清楚。我们通过MTT测定、实时逆转录聚合酶链反应（RT-PCR）测定、蛋白质印迹测定、免疫沉淀（ChIP）测定、免疫组织化学和表观遗传酶活性分析评估了GE对ERα再激活的体外和体内表观遗传效应。使用包括异种移植和自发性乳腺癌小鼠模型在内的临床前小鼠模型来测试GE在体内的功效。我们发现，在 ERα 阴性 MDA-MB-231 乳腺癌细胞中，GE 可以重新激活 ERα 表达，并且当与组蛋白脱乙酰酶 (HDAC) 抑制剂曲古抑菌素 A (TSA) 联合使用时，这种效应会协同增强。 GE 治疗还使 ERα 依赖性细胞对激活剂 17β-雌二醇 (E2) 和拮抗剂 TAM 的反应重新敏感。进一步的研究表明，GE 可以导致 ERα 启动子中染色质结构的重塑，从而有助于 ERα 重新激活。一致的是，膳食 GE 显着预防癌症的发展并减少 ERα 阴性小鼠乳腺肿瘤的生长。膳食 GE 进一步增强了 TAM 诱导的抗癌功效，至少部分归因于表观遗传 ERα 的重新激活。我们的研究表明，大豆金雀异黄酮可以表观遗传恢复 ERα 表达，从而增加体外和体内 TAM 依赖性抗雌激素治疗的敏感性。我们的研究结果揭示了一种使用生物活性大豆产品和抗激素疗法治疗难治性 ERα 阴性乳腺癌的新型治疗组合方法，这将为乳腺癌治疗提供更有效的选择。
Estrogen receptor-α (ERα)-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 ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown. We have evaluated the in vitro and in vivo epigenetic effects of GE on ERα 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. We found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERα-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERα-dependent cellular responses to activator 17β-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERα promoter thereby contributing to ERα reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERα-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERα reactivation. Our studies suggest that soybean genistein can epigenetically restore ERα 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 ERα-negative breast cancer which will provide more effective options in breast cancer therapy.
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DOI：
10.1073/pnas.90.7.2690
发表时间：
1993-04-01
影响因子：
11.1
作者：
FOTSIS, T;PEPPER, M;SCHWEIGERER, L
通讯作者：
SCHWEIGERER, L
影响因子：
11.2
作者：
Majid, Shahana;Kikuno, Nobuyuki;Dahiya, Rajvir
通讯作者：
Dahiya, Rajvir
影响因子：
4.1
作者：
Fritz, WA;Wang, J;Lamartiniere, CA
通讯作者：
Lamartiniere, CA
影响因子：
4.2
作者：
Day, JK;Bauer, AM;Lubahn, DB
通讯作者：
Lubahn, DB
影响因子：
4.7
作者：
Mai, Zhiming;Blackburn, George L.;Zhou, Jin-Rong
通讯作者：
Zhou, Jin-Rong