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Elucidating the Molecular Mechanisms of Zoledronic Acid in Breast Cancer.

机译：阐明唑来膦酸在乳腺癌中的分子机制。

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摘要

Zoledronic acid (ZA) has been shown to improve disease free survival of postmenopausal breast cancer patients when used alone or in combination with endocrine therapy. These effects have been corroborated by many preclinical studies. Furthermore, ZA has been shown to reduce metastatic disease in patients, which has also been reproduced in the preclinical setting. However, the molecular mechanisms explicating these pharmacological effects of ZA remain unknown. As such, the objective of this dissertation was to elucidate the molecular mechanisms of ZA on cell viability, the epithelial-mesenchymal transition (EMT), and the tumor initiating cell population.;Experiments investigating the combination of ZA and aromatase inhibitor letrozole showed that the combination inhibited cell viability in an additive manner. Further examination into the mechanism of this combination effect unveiled the inhibitory effects of ZA on the aromatase enzyme. Immunoprecipitation experiments confirmed that ZA inhibited serine phosphorylation of the enzyme important for its enzymatic activity. Rescue experiments showed that estradiol treatment could prevent loss of cell viability after ZA treatment, suggesting that ZA's inhibition of the aromatase enzyme contributes to the anti-tumor mechanism of ZA. Other mechanisms of ZA's anti-tumor effect were also investigated. Although treatment with ZA inhibited the expression and enzymatic activity of cyclooxygenase-2, as well as the transcriptional activation of nuclear factor kappa B, neither were involved in ZA's inhibition of cell viability.;However, treatment with ZA modulated EMT in triple negative breast cancer cell lines, as evidenced by decreased mesenchymal cellular morphology, decreased mesenchymal mRNA and protein expression. This was accompanied by increased E-cadherin protein, mRNA, and CD24 cell surface expression. Furthermore, this reversal in EMT was attributed to inhibition of nuclear factor kappa B transcriptional control. Additionally, ZA treatment decreased the self renewal capability of triple negative breast cancer cells, as evidenced by decreased self renewal protein expression. Furthermore, treatment with ZA both prevented mammosphere formation and decreased the number of existing mammospheres. These results suggest that treatment with ZA can prevent the acquisition of an invasive phenotype as well as the capacity to repopulate a tumor at a secondary site, thereby eliminating a cancer cell's ability to metastasize.
机译：唑来膦酸（ZA）单独使用或与内分泌疗法联合使用时，可改善绝经后乳腺癌患者的无病生存期。许多临床前研究证实了这些作用。此外，ZA已显示可减少患者的转移性疾病，在临床前环境中也已再现。然而，尚不清楚ZA的这些药理作用的分子机制。因此，本论文的目的是阐明ZA对细胞活力，上皮-间质转化（EMT）和肿瘤起始细胞群体的分子机制。;对ZA和芳香酶抑制剂来曲唑的组合进行的实验研究表明，ZA组合以加性方式抑制细胞活力。进一步研究这种联合作用的机理揭示了ZA对芳香酶的抑制作用。免疫沉淀实验证实，ZA抑制了丝氨酸磷酸化酶的重要酶活性。救援实验表明，雌二醇处理可以防止ZA处理后细胞活力的丧失，这表明ZA对芳香酶的抑制作用有助于ZA的抗肿瘤机制。还研究了ZA抗肿瘤作用的其他机制。尽管用ZA处理可抑制环氧合酶2的表达和酶活性以及核因子kappa B的转录激活，但两者均不影响ZA抑制细胞活力。如间充质细胞形态降低所证明的，细胞系间充质mRNA和蛋白质表达降低。这伴随着E-钙粘蛋白，mRNA和CD24细胞表面表达的增加。此外，EMT中的这种逆转归因于对核因子κB转录控制的抑制。另外，ZA治疗降低了三阴性乳腺癌细胞的自我更新能力，这由减少的自我更新蛋白表达所证明。此外，用ZA处理既防止了乳球形成，又减少了现有乳球的数量。这些结果表明，用ZA治疗可以防止侵袭性表型的获得以及在第二位点再增殖肿瘤的能力，从而消除了癌细胞的转移能力。

著录项

  • 作者

    Schech, Amanda J.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Pharmacology.;Biology Molecular.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 164 p.
  • 总页数 164
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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