ANTIESTROGEN REGULATION OF QUINONE REDUCTASE

醌还原酶的抗雌激素调节

• 批准号: 6522491
• 负责人: MONICA MONTANO
• 金额: $ 15.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522491
• 关键词: BCL2 gene /protein; DNA footprinting; MCF7 cell; NAD(P)H dehydrogenase; breast neoplasms; cell proliferation; enzyme activity; estrogen inhibitor; gel mobility shift assay; genetic transcription; glutathione transferase; hormone regulation /control mechanism; metallothionein; neoplasm /cancer chemotherapy; protein binding; yeast two hybrid system

Antiestrogens are used widely in the treatment of breast cancer and are thought to function as anticancer drugs primarily by inhibiting estradiol-stimulated tumor growth. We have recently observed that quinone reductase (QR) activity is increased in breast cancer cells by antiestrogens via an estrogen receptor (ER)-dependent mechanism. The increase in QR by antiestrogen may provide protective effects against the toxicity and mutagenicity caused by quinones, and contribute to the beneficial antioxidant and anticancer activities of antiestrogens. Since QR can also metabolize and activate chemotherapeutic quinones, antiestrogens may increase the effectiveness of chemotherapeutic agents that are activated by QR. I therefore propose to test the following hypothesis: ER-dependent pathways for antiestrogens and the ER- independent pathway for electrophiles may merge in a common mechanism at the level of nuclear protein binding to the electrophile/antioxidant response elements (EpRE/AREs) leading to the activation of QR and possibly other EpRE-containing genes. We further propose that antiestrogen-mediated stimulation of QR will potentiate the responsiveness of breast cancer cells to chemotherapeutic agents that are activated by QR. The specific aims of this proposal are to: (1) determine the mechanism of antiestrogen-mediated activation of QR; (2) determine if antiestrogens can activate other detoxifying enzymes and other proteins that are known to be transcriptionally regulated through EpREs; and (3) determine if antiestrogens increase the sensitivity of breast cancer cells to bioreductive chemotherapeutic agents that are activated by QR. It is anticipated that these studies will provide new insight as to how antiestrogens function as anticancer agents and increase our understanding of the regulation of detoxifying enzymes and other proteins whose transcription is under the control of EpRE/AREs.

抗雌激素广泛用于治疗乳腺癌，是 被认为主要是通过抑制作用作为抗癌药物 雌二醇刺激的肿瘤生长。 我们最近观察到 在乳腺癌细胞中，喹酮还原酶（QR）的活性通过 抗雌激素通过雌激素受体（ER）依赖性机制。 这 抗雌激素增加QR可能会提供针对的保护作用 奎因酮引起的毒性和诱变，并有助于 抗雌激素的有益抗氧化剂和抗癌活性。 由于QR也可以代谢并激活化学治疗性奎因酮，因此 抗雌激素可能会提高化学治疗剂的有效性 由QR激活。 因此，我建议测试以下 假设：抗雌激素和ER-的ER依赖性途径 电泳的独立途径可以合并为公共机制 在核蛋白与亲电/抗氧化剂的结合水平上 响应元素（EPRE/ARES）导致QR激活 可能是其他含Epre的基因。我们进一步提出 抗雌激素介导的QR刺激将增强 乳腺癌细胞对化学治疗剂的反应性 被QR激活。 该提案的具体目的是：（1）确定机制 抗雌激素介导的QR激活； （2）确定是否 抗雌激素可以激活其他排毒酶和其他蛋白质 已知通过EPRES进行了转录调节； （3） 确定抗雌激素是否会增加乳腺癌的敏感性 通过QR激活的生物学化学治疗剂的细胞。 可以预料，这些研究将为如何提供新的见解 抗雌激素充当抗癌剂，并增加我们的 了解排毒酶和其他的调节 转录的蛋白质在Epre/Ares的控制之下。