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Bcl-2 family function in antiestrogen-resistant breast cancer cells.

机译:Bcl-2家族在抗雌激素抗性乳腺癌细胞中起作用。

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摘要

Antiestrogen treatment is often the therapy of choice for women with estrogen receptor-positive (ER+) breast cancer. Tamoxifen (TAM), one of the most widely used antiestrogens in breast cancer therapy, improves disease-free as well as overall survival in most ER+ breast cancer patients. The steroidal antiestrogen, ICI 182,780 (ICI), is a pure antagonist of the ER and is often effective as a second-line treatment for women who do not respond to TAM. Unfortunately, the development of resistance to both of these antiestrogen therapies is an overwhelming concern in the clinic. We and others have demonstrated that antiestrogens can regulate apoptosis by altering the expression of BCL2 family members, but the effects of TAM and ICI are not always consistent. Therefore, we hypothesize that the deregulation of Bcl-2 expression is a critical step in developing antiestrogen resistance, but that these antiestrogen-resistant breast cancer cells are now more susceptible to cell death induced by Bcl-2 inhibitors.;We now report that baseline and antiestrogen treated expression of the anti-apoptotic proteins Bcl-2 and Bcl-w is increased in the ICI/TAM-resistant breast cancer cells, with deregulation of expression occurring at the level of transcription. We also observed that AP-1, a transcription factor with binding sites on the Bcl-2 promoter, is overexpressed in ICI treated resistant cells. After examining antiapoptotic Bcl-2 protein expression in a model of TAM only resistance, we found that there is no change in Bcl-2 or Bcl-w in the TAM-resistant MCF7/RR cell line as compared to MCF7 cells.;We also determined that the inhibition of Bcl-2 and Bcl-w increases ICI sensitivity in sensitive cells and restores ICI sensitivity in the resistant cells, with no effect seen following TAM treatment. However, in ICI-resistant cells we found that co-inhibiting Bcl-2 and Bcl-w increased both autophagy and necrosis, not apoptosis. We also found that inhibiting autophagy does not further decrease cell proliferation; however, there is a decrease in necrosis and an increase in apoptosis. Thus, we conclude that the altered expression of Bcl-2 family proteins may promote the development of acquired antiestrogen resistance by allowing breast cancer cells to evade cell death when undergoing antiestrogen treatment.
机译:抗雌激素治疗通常是雌激素受体阳性(ER +)乳腺癌女性的首选治疗方法。他莫昔芬(TAM)是乳腺癌治疗中使用最广泛的抗雌激素之一,可改善大多数ER +乳腺癌患者的无病生存率和总体生存率。甾体抗雌激素药ICI 182,780(ICI)是ER的纯拮抗剂,通常可作为对TAM无反应的女性的二线治疗。不幸的是,对这两种抗雌激素疗法的抗药性的发展是临床上的压倒性关注。我们和其他人证明抗雌激素药可以通过改变BCL2家族成员的表达来调节细胞凋亡,但是TAM和ICI的作用并不总是一致的。因此,我们假设Bcl-2表达的失调是发展抗雌激素性的关键步骤,但是这些抗雌激素性的乳腺癌细胞现在更容易受到Bcl-2抑制剂诱导的细胞死亡的影响。在抗ICI / TAM的乳腺癌细胞中,抗​​雌激素处理的抗凋亡蛋白Bcl-2和Bcl-w的表达增加,并且在转录水平上表达失调。我们还观察到AP-1,一种在Bcl-2启动子上具有结合位点的转录因子,在ICI处理的抗性细胞中过表达。在仅TAM耐药模型中检查了抗凋亡Bcl-2蛋白的表达后,我们发现与MCF7细胞相比,在TAM耐药MCF7 / RR细胞系中Bcl-2或Bcl-w没有变化。研究人员发现,抑制Bcl-2和Bcl-w可以增加敏感细胞的ICI敏感性,并恢复耐药细胞的ICI敏感性,而TAM处理后未见效果。然而,在ICI抗性细胞中,我们发现共抑制Bcl-2和Bcl-w增加了自噬和坏死,而不是凋亡。我们还发现抑制自噬不会进一步降低细胞增殖。然而,坏死的减少和细胞凋亡的增加。因此,我们得出结论,Bcl-2家族蛋白表达的改变可能通过使乳腺癌细胞在接受抗雌激素治疗时逃避细胞死亡而促进获得性抗雌激素耐药性的发展。

著录项

  • 作者

    Crawford, Anatasha Carissa.;

  • 作者单位

    Georgetown University.;

  • 授予单位 Georgetown University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 231 p.
  • 总页数 231
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

  • 入库时间 2022-08-17 11:37:38

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