Estrogen receptor, p38 MAPKs and topo IIa in breast cancer

乳腺癌中的雌激素受体、p38 MAPK 和拓扑 IIa

• 批准号: 8391116
• 负责人: GUAN CHEN
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391116
• 关键词: Accounting; Attenuated; Binding; Breast Cancer Cell; Breast Cancer Model; Cancer Patient; Cell Culture Techniques; Cell Death; Country; Couples; DNA; DNA Topoisomerases; Disease; Doctor of Philosophy; Dominant-Negative Mutation; Drug toxicity; Engineering; Enrollment; Estrogen Receptor 2; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Female; Funding; Gene Expression; Growth; Healthcare; Healthcare Systems; Human; In Vitro; JUN gene; Link; MAP Kinase Gene; MAPK14 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Military Personnel; Mus; Nude Mice; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Protein Family; Proteins; Protocols documentation; Publishing; Receptor Cell; Receptor Signaling; Research; Research Personnel; Resistance; Role; Services; Signal Transduction; Stress; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Topoisomerase; Topoisomerase II; Toxic effect; Toxin; Transactivation; Veterans; Woman; Work; arm; base; cancer therapy; cancer type; care systems; cellular targeting; chemotherapeutic agent; chemotherapy; drug sensitivity; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; multicatalytic endopeptidase complex; novel; novel therapeutics; protein expression; public health relevance; receptor expression; research study; response; therapeutic development; therapeutic target; tumor

DESCRIPTION (provided by applicant): Estrogen receptor (ER) mediates estrogen signaling to promote breast cancer growth and thereby serves as a target for hormone therapy in ER+ breast cancer. DNA topoisomerase II1 (topo II1), on the other hand, maintains proper DNA topology and acts as a therapeutic target for both ER+ and ER- breast cancer. Although levels of intrinsic topo II1 protein correlate with sensitivity to its inhibitors, this protein is frequently depleted by its toxins and information about how topo II1 is maintained during the therapeutic stress is missing. p38 MAPKs consist of 1, 2, 3, and 4 proteins that are major kinase cascades to determine cellular response to upstream signals through regulating gene expressions. We showed during the past funding period that ER inhibits stress-induced cell death via c-Jun binding and our recent work further showed that ER specifically suppresses topo II drug-induced growth inhibition by attenuating p38 stimulations of topo II1 expression. It is proposed here that p38 MAPK activations maintain topo II1 expression that is antagonized by ER signaling, leading to increased topo II-drug toxicity in ER- breast cancer. This hypothesis is based on our preliminary studies showing 1) topo II inhibitors, but not taxol, are more potent in inhibiting ER- breast cancer growth that couples with increased intrinsic p383 but not topo II1 protein expression; 2) there are also increased p381 phosphorylations linked to resistance of topo II1 proteins to topo drug-induced depletion in ER- over ER+ cells, indicating a topo II1 maintaining activity of both p381 and p383 that is antagonized by ER signaling; 3) p383 antagonizes ER through binding / phosphorylating ER at S118; 4) p381 and p383 trans- activate topo II1 in ER- but not ER+ breast cancer but 5) only p381 binds to topo II1 protein. These results together suggest that p38 MAPKs maintain topo II1 expression that is suppressed by ER signaling leading to a sustained topo II1 protein expression and increased topo II drug toxicity in ER- breast cancer. Experiments in this second funding period will demonstrate if 1) p381 and p383 cooperate to maintain topo II1 protein expression through their over-expression in ER+ and depletion in ER- breast cancer, 2) ER antagonizes p381/p383 stimulations of topo II1 expression by directly binding p383 proteins and indirectly attenuating p381 phosphorylation; and 3) p38 MAPK activities determine the growth-inhibitory efficacy of topo II drugs against human breast cancer in vitro and in mice. Topo II inhibitor-containing chemotherapy is known for its higher therapeutic activity against ER- breast cancer for several decades and mechanism involved for this selectivity however remains unknown. This proposal will test the hypothesis that p38 MAPK activation in breast cancer acts to maintain topo II1 protein expression during therapeutic stress that is antagonized by ER signaling leading to increased topo II drug activity in ER- breast cancer. These studies will reveal a novel function of p38 stress MAPKs in regulating topo II1 expression through cross-talking with ER signaling and results obtained will contribute significantly to breast cancer therapy.

描述（由申请人提供）： 雌激素受体 (ER) 介导雌激素信号传导以促进乳腺癌生长，从而成为 ER+ 乳腺癌激素治疗的靶点。另一方面，DNA 拓扑异构酶 II1 (topo II1) 维持正确的 DNA 拓扑结构，并作为 ER+ 和 ER- 乳腺癌的治疗靶点。尽管内在拓扑 II1 蛋白的水平与其抑制剂的敏感性相关，但该蛋白经常被其毒素耗尽，并且关于如何在治疗应激期间维持拓扑 II1 的信息缺失。 p38 MAPK 由 1、2、3 和 4 种蛋白质组成，它们是主要的激酶级联，通过调节基因表达来确定细胞对上游信号的反应。我们在过去的资助期间表明，ER 通过 c-Jun 结合抑制应激诱导的细胞死亡，我们最近的工作进一步表明，ER 通过减弱 p38 对 topo II1 表达的刺激，特异性抑制 topo II 药物诱导的生长抑制。 这里提出，p38 MAPK 激活维持了被 ER 信号传导拮抗的拓扑 II1 表达，导致 ER 乳腺癌中拓扑 II 药物毒性增加。这一假设基于我们的初步研究，显示 1) topo II 抑制剂（而非紫杉醇）更有效地抑制 ER-乳腺癌生长，与内在 p383 蛋白表达增加相关，但与 topo II1 蛋白表达无关； 2) 在 ER- 细胞中，p381 磷酸化也增加，这与 topo II1 蛋白对 ER- 细胞中 topo 药物诱导的耗竭的抵抗有关，这表明 topo II1 维持了 p381 和 p383 的活性，而 p381 和 p383 被 ER 信号传导拮抗； 3) p383通过在S118处结合/磷酸化ER来拮抗ER； 4) p381 和 p383 在 ER- 而非 ER+ 乳腺癌中反式激活拓扑 II1，但 5) 只有 p381 与拓扑 II1 蛋白结合。这些结果共同表明，p38 MAPK 维持被 ER 信号传导抑制的拓扑 II1 表达，导致 ER 乳腺癌中拓扑 II1 蛋白持续表达并增加拓扑 II 药物毒性。 第二个资助期的实验将证明：1) p381 和 p383 通过在 ER+ 中过度表达和 ER- 乳腺癌中的缺失来合作维持拓扑 II1 蛋白表达，2) ER 通过直接结合 p383 蛋白并间接减弱 p381 磷酸化来拮抗 p381/p383 对拓扑 II1 表达的刺激； 3) p38 MAPK 活性决定了拓扑 II 药物在体外和小鼠体内对人乳腺癌的生长抑制功效。几十年来，含有拓扑 II 抑制剂的化疗因其对 ER-乳腺癌的较高治疗活性而闻名，但这种选择性所涉及的机制仍然未知。该提案将检验以下假设：乳腺癌中 p38 MAPK 激活可在治疗应激期间维持 topo II1 蛋白表达，该表达被 ER 信号传导拮抗，从而导致 ER-乳腺癌中 topo II 药物活性增加。这些研究将揭示 p38 应激 MAPK 通过与 ER 信号传导相互作用调节 topo II1 表达的新功能，所获得的结果将对乳腺癌治疗做出重大贡献。