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首页> 外文学位 >Improving the efficacy of hormonal therapy in MCF-7 breast cancer cells grown in the presence of IGF-I by targeting the MAPK/MEK and JAK/STAT cell survival signaling pathways.
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Improving the efficacy of hormonal therapy in MCF-7 breast cancer cells grown in the presence of IGF-I by targeting the MAPK/MEK and JAK/STAT cell survival signaling pathways.

机译：通过靶向MAPK / MEK和JAK / STAT细胞存活信号通路，改善激素治疗在IGF-1存在下生长的MCF-7乳腺癌细胞中的功效。

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摘要

Breast cancer is the leading cause of cancer and the second leading cause of cancer deaths in women in the United States. Approximately 30% of estrogen receptor positive breast cancers are inherently resistant to anti-estrogen therapy and the recurrence of breast cancer in women initially responsive to anti-estrogen treatment frequently occurs. Thus, new approaches to increase the efficacy of hormonal therapy are needed. Because epidemiological studies associate high IGF-I levels with a poor prognosis for breast cancer patients, we investigated the underlying mechanism(s) of IGF-I-mediated protection. 4-Hydroxytamoxifen-and mifepristone-induced cell death is significantly attenuated by IGF-I. IGF-I induction of cell survival pathways was analyzed focusing on signaling pathways and it has been demonstrated that IGF-I-mediated protection of MCF-7 cells resulted from activation of the MAPK/MEK and JAK/STAT signaling pathways. Cell lifting and PARP cleavage was detected in tamoxifen-and mifepristone-treated MCF-7 cells growing in the presence of IGF-I and PD98059, a MEK inhibitor and also in the presence of IGF-I and AG490, a JAK2 inhibitor. The amount of cleaved PARP in MCF-7 cells transfected with MEK1siRNA is higher in cells treated with estradiol alone than with hormonal therapy. The MEK1siRNA may cause growth arrest, interfering with the actions of the hormonal therapy. The degree of death caused by hormonal therapy in the absence and presence of IGF-I is similar indicating that MEK1 has a role in the protection of MCF-7 cells from hormonal therapy-induced cell death. Transfection of MCF-7 cells with dominant-negative JAK2 resulted in increased cell death. The JAK/STAT pathway appears to be an important pathway for the survival of breast cancer cells because even in the absence of hormonal therapy, as was evident by the death of the MCF-7 cells with the dominant-negative JAK2 constructs. Higher levels of PARP cleavage are present in MCF-7 cells transfected with JAK2siRNA. These pre-clinical in vitro studies provide a mechanistic rationale to why high circulating levels of IGF-I may seriously impact the progression of breast cancer and its response to hormonal therapy and why the efficacy of hormonal therapy of breast cancer can be significantly improved by simultaneously targeting these signaling pathway.
机译：在美国，乳腺癌是癌症的主要原因，也是癌症死亡的第二大原因。大约30％的雌激素受体阳性乳腺癌固有地对抗雌激素治疗有抗性，并且最初对抗雌激素治疗有反应的女性经常发生乳腺癌复发。因此，需要增加激素治疗功效的新方法。因为流行病学研究将高IGF-I水平与乳腺癌患者的不良预后相关联，所以我们研究了IGF-I介导的保护的潜在机制。 IGF-I显着减轻了4-羟基他莫昔芬和米非司酮诱导的细胞死亡。分析了IGF-I对细胞存活途径的诱导，着眼于信号传导途径，并且已经证明IGF-I介导的对MCF-7细胞的保护是由MAPK / MEK和JAK / STAT信号传导途径的激活引起的。在他莫昔芬和米非司酮处理的MCF-7细胞中，在存在IGF-1和MEK抑制剂PD98059以及存在IGF-1和JAK2抑制剂AG490的情况下生长的MCF-7细胞中，检测到了细胞提升和PARP裂解。在单独用雌二醇处理的细胞中，经MEK1siRNA转染的MCF-7细胞中裂解的PARP量高于激素治疗。 MEK1siRNA可能会导致生长停滞，干扰激素治疗的作用。在不存在和存在IGF-1的情况下，激素治疗引起的死亡程度相似，这表明MEK1在保护MCF-7细胞免受激素治疗诱导的细胞死亡中起作用。用显性阴性JAK2转染MCF-7细胞导致细胞死亡增加。 JAK / STAT途径似乎是乳腺癌细胞存活的重要途径，因为即使在没有激素治疗的情况下，如显性阴性JAK2构建体的MCF-7细胞死亡，也证明了这一点。用JAK2siRNA转染的MCF-7细胞中存在更高水平的PARP裂解。这些临床前的体外研究为为什么高循环水平的IGF-I可能严重影响乳腺癌的进展及其对激素治疗的反应以及为何同时可以显着提高乳腺癌激素治疗的疗效提供了机械原理。针对这些信号通路。

著录项

  • 作者

    Welborn, April Eve.;

  • 作者单位

    Medical College of Georgia.;

  • 授予单位 Medical College of Georgia.;
  • 学科 Biology Molecular.; Biology Cell.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 92 p.
  • 总页数 92
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;生物化学;
  • 关键词

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