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首页> 外文学位 >The Role of Darpp-32 and t-Darpp in Breast Cancer Tumorigenesis and the Development of Acquired Drug Resistance.
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The Role of Darpp-32 and t-Darpp in Breast Cancer Tumorigenesis and the Development of Acquired Drug Resistance.

机译：Darpp-32和t-Darpp在乳腺癌肿瘤发生和获得性耐药发展中的作用。

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摘要

Each year approximately 233,000 women in the United States are diagnosed with breast cancer. Survival depends greatly not only on the grade and stage of the cancer at diagnosis, but also on the molecular type of breast cancer. Around 20-25% of women with breast cancer overexpress the human epidermal growth factor receptor 2 (HER2) and are diagnosed with HER2-positive breast cancer. Overexpression of HER2 stimulates malignant growth and survival. Currently there are four FDA-approved drugs targeted to HER2; however, women with this type of cancer continue to have a poor prognosis and low disease-free survival rate, largely because acquired resistance to targeted therapies develops so rapidly. In order to improve cancer patient outcomes it is imperative that we identify novel therapeutic targets.;Upregulation of the protein t-Darpp (truncated variant of Darpp-32) has been linked directly to resistance to trastuzumab (HerceptinRTM), a well-established treatment for HER2-positive breast cancer. The full-length protein Darpp-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) reverses the trastuzumab resistance phenotype induced by t-Darpp. This suggests that these two proteins have antagonistic functions in determining a cell's sensitivity to trastuzumab and possibly in breast cancer in general. Our research goal was to better understand the role of Darpp-32 and t-Darpp in tumor development and progression.;In order to determine the role of Darpp-32 and t-Darpp in tumor development, Darpp-32 and t-Darpp expression in healthy and tumorigenic mouse mammary tissue was examined. We observed a predominance of Darpp-32 in healthy breast tissue and a predominance of t-Darpp in tumor breast tissue. Using Darpp-32/t-Darpp knockout mice, crossed with a mouse mammary tumor model, we showed that these proteins are linked to increased tumor growth. Together, these data suggest that t-Darpp, and to a lesser degree Darpp-32, are directly involved in breast tumor development.;In order to investigate the role of Darpp-32 and t-Darpp in tumor progression, we examined their involvement in resistance to another HER2-targeted therapy, lapatinib (TykerbRTM). Western and RT-PCR analysis showed that lapatinib-resistant cells exhibited a shift in their relative levels of Darpp-32 and t-Darpp toward a predominance of t-Darpp in resistant cells, as compared to parental cells. While overexpression of t-Darpp was insufficient to cause de novo lapatinib resistance in a short-term cell proliferation assay, it was enough to confer a survival and/or growth advantage during prolonged exposure to drug. The mechanism responsible for this survival advantage is not well understood, but it may be linked to failed lapatinib-induced upregulation of the pro-apoptotic protein BIM in cells overexpressing t-Darpp.;Relative levels of Darpp-32 and t-Darpp seem to be important in breast cancer growth and drug resistance, and shifts in expression from Darpp-32 to t-Darpp occur relatively quickly, suggesting a potential epigenetic mechanism of gene regulation. Hypomethylation of DNA in human breast cancer cell lines caused the upregulation of Darpp-32. This evidence suggests that DNA methylation plays a role in regulating gene expression at this locus. A better understanding of the mechanisms regulating Darpp-32 and t-Darpp expression as well as their relative functions in tumorigenesis and drug resistance has the potential to improve patient outcomes.
机译：在美国，每年大约有233,000名女性被诊断出患有乳腺癌。存活率不仅取决于诊断时癌症的级别和阶段，而且还取决于乳腺癌的分子类型。约有20-25％的乳腺癌女性过度表达人类表皮生长因子受体2（HER2），并被诊断为HER2阳性乳腺癌。 HER2的过表达刺激恶性生长和生存。当前有四种针对HER2的FDA批准药物；然而，患有这种类型癌症的妇女预后仍然很差，无病生存率很低，这在很大程度上是因为对靶向疗法的后天抵抗力发展如此迅速。为了改善癌症患者的预后，我们必须确定新的治疗靶标。t-Darpp蛋白（Darpp-32的截短变体）的上调已直接与对曲妥珠单抗（HerceptinRTM）的耐药性直接相关用于HER2阳性乳腺癌。全长蛋白Darpp-32（多巴胺和cAMP调节的32kDa磷酸蛋白）逆转了由t-Darpp诱导的曲妥珠单抗耐药表型。这表明这两种蛋白在确定细胞对曲妥珠单抗的敏感性以及总体上可能对乳腺癌的敏感性方面具有拮抗作用。我们的研究目标是更好地了解Darpp-32和t-Darpp在肿瘤发展和进展中的作用。；为了确定Darpp-32和t-Darpp在肿瘤发展，Darpp-32和t-Darpp表达中的作用在健康和致瘤小鼠的乳腺组织中进行了检查。我们观察到在健康的乳腺组织中主要存在Darpp-32，而在肿瘤乳腺组织中主要存在t-Darpp。使用与小鼠乳腺肿瘤模型杂交的Darpp-32 / t-Darpp基因敲除小鼠，我们显示这些蛋白与肿瘤生长增加有关。总之，这些数据表明t-Darpp和较小程度的Darpp-32直接参与了乳腺肿瘤的发展。为了研究Darpp-32和t-Darpp在肿瘤进展中的作用，我们检查了它们的参与对另一种以HER2靶向的治疗药物拉帕替尼（TykerbRTM）具有抗药性。 Western和RT-PCR分析显示，与亲代细胞相比，抗拉帕替尼的细胞相对于抗细胞，其Darpp-32和t-Darpp的相对水平向t-Darpp的优势转移。尽管在短期细胞增殖试验中，t-Darpp的过表达不足以引起新的拉帕替尼耐药，但足以在长期暴露于药物的情况下提供生存和/或生长优势。导致这种存活优势的机制尚不十分清楚，但它可能与拉帕替尼诱导的过表达t-Darpp的细胞中促凋亡蛋白BIM的上调失败有关； Darpp-32和t-Darpp的相对水平似乎与在乳腺癌的生长和耐药中起重要作用，并且从Darpp-32到t-Darpp的表达变化相对较快地发生，这提示了潜在的表观遗传调控机制。人乳腺癌细胞系中DNA的甲基化不足导致Darpp-32的上调。该证据表明DNA甲基化在该基因座上调节基因表达中起作用。对调节Darpp-32和t-Darpp表达的机制及其在肿瘤发生和耐药中的相对功能的更好理解，可能会改善患者的预后。

著录项

  • 作者

    Christenson, Jessica Lynn.;

  • 作者单位

    City of Hope's Irell & Manella Graduate School of Biomedical Sciences.;

  • 授予单位 City of Hope's Irell & Manella Graduate School of Biomedical Sciences.;
  • 学科 Molecular biology.;Oncology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 129 p.
  • 总页数 129
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 S-4;
  • 关键词

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