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首页> 外文学位 >The Hsp90 co-chaperone p23 as a regulator and prognostic indicator in breast cancer.
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The Hsp90 co-chaperone p23 as a regulator and prognostic indicator in breast cancer.

机译：Hsp90伴侣蛋白p23作为乳腺癌的调节剂和预后指标。

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摘要

p23 is an Hsp90 co-chaperone that stabilizes estrogen binding to the nuclear hormone receptor estrogen receptor alpha (ERalpha) so that ERalpha can efficiently activate transcription of target genes. p23 also modulates receptor binding to DNA. Previous work has shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion through matrigel without affecting the estrogen-dependent proliferative response, suggesting that p23 affects late, rather than early stages of breast cancer development. To gain a comprehensive view of the effects of p23 on ERalpha dependent and ERalpha independent pathways, gene expression profiling was performed on control versus MCF-7+p23 cells with or without estrogen treatment. A number of p23 sensitive genes involved in metastasis and drug resistance were identified, which differed regarding sensitivity to estrogen treatment. Most striking is that many p23 sensitive genes are also misregulated in late stage breast cancers. Several genes were investigated and ABCC3, an ATP-dependent transporter, was examined further because of its role as a multidrug resistance protein. MCF-7+p23 cells upregulate expression of ABCC3 and are also selectively resistant to the chemotherapeutic agents etoposide and doxorubicin. Also, certain p23 upregulated genes are not inactivated by the Hsp90 inhibitor and chemotherapeutic agent 17-AAG, suggesting a novel Hsp90--independent role for p23 in gene regulation and tumorigenesis. These observations present p23 as an important regulator of chemotherapeutic resistance in ERalpha-positive (ERalpha+) late stage breast cancers. Further, p23 may regulate many pathways that drive tumorigenesis in ERalpha-negative (ERalpha-) breast cancers since, surprisingly, ER inversely regulates many p23 sensitive genes. p23 expression and localization were also examined in mouse mammary development and in both ERalpha+ and ERalpha- human breast tumor samples. p23 expression is both nuclear and cytoplasmic throughout mammary development, with nuclear p23 expression decreasing at lactation. Interestingly, abundant cytoplasmic p23 localization in human breast cancer patients correlates with shorter disease free survival. Taken together, these data reveal cytoplasmic p23 as a prognostic indicator and cytoplasmic p23 sensitive pathways as plausible therapeutic targets in ERalpha+ and ERalpha-breast cancers.
机译：p23是一种Hsp90伴侣蛋白，可稳定雌激素与核激素受体雌激素受体α（ERalpha）的结合，从而使ERalpha可以有效激活靶基因的转录。 p23还调节受体与DNA的结合。先前的工作表明，过度表达p23的MCF-7细胞（MCF-7 + p23）表现出通过基质胶的侵袭增加，而不影响雌激素依赖性增殖反应，这表明p23影响乳腺癌发展的晚期而非早期。为了全面了解p23对ERalpha依赖性和ERalpha依赖性途径的影响，在有或没有雌激素治疗的对照组和MCF-7 + p23细胞上进行了基因表达谱分析。鉴定出许多与转移和耐药有关的p23敏感基因，它们对雌激素治疗的敏感性不同。最惊人的是，许多p23敏感基因在晚期乳腺癌中也被错误调节。研究了几个基因，并进一步研究了ABCC3（一种ATP依赖的转运蛋白），因为它是一种多药耐药蛋白。 MCF-7 + p23细胞上调ABCC3的表达，并且对化疗药物依托泊苷和阿霉素有选择性的抗性。同样，某些p23上调的基因不会被Hsp90抑制剂和化学治疗剂17-AAG灭活，这表明p23在基因调控和肿瘤发生中具有新的Hsp90独立作用。这些观察结果表明p23是ERalpha阳性（ERalpha +）晚期乳腺癌对化疗药物耐药性的重要调节剂。此外，p23可能调控许多驱动ERalpha阴性（ERalpha-）乳腺癌的肿瘤发生的途径，因为令人惊讶的是，ER反向调控了许多p23敏感基因。在小鼠乳腺发育以及ERalpha +和ERalpha-人乳腺肿瘤样品中也检查了p23的表达和定位。在整个乳腺发育过程中，p23的表达都是核和细胞质的，在哺乳期p23的表达减少。有趣的是，人类乳腺癌患者中丰富的细胞质p23定位与较短的无病生存时间相关。综上所述，这些数据揭示了细胞质p23作为预后指标，而细胞质p23敏感途径是ERalpha +和ERalpha-乳腺癌的合理治疗靶标。

著录项

  • 作者

    Simpson, Natalie E.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.;Health Sciences Oncology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 178 p.
  • 总页数 178
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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