Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint.
Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint.
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DOI：
10.1007/s10549-011-1399-0
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发表时间：
2012-01
影响因子：
3.8
通讯作者：
Jacobsen, Britta M.
中科院分区：
文献类型：
--
作者：
Badtke, Melanie M.;Jambal, Purevsuren;Dye, Wendy W.;Spillman, Monique A.;Post, Miriam D.;Horwitz, Kathryn B.;Jacobsen, Britta M.
是否类固醇受体在乳腺癌腔的存在，使他们耐紫杉烷仍然不确定。在这里，我们评估的作用，孕激素受体（PR）对紫杉烷诱导的细胞死亡。我们以前表明，雌激素受体（ER）阳性的人乳腺癌细胞，诱导表达PR-A或PR-B亚型的紫杉烷刺激的细胞凋亡相比，相同的细胞缺乏PR。令人惊讶的是，PR依赖的保护发生在孕酮的情况下，表明unliganded受体的生物活性。目前的研究表明，未配体PR，集中在PR-A，保护乳腺癌细胞免受紫杉烷刺激的凋亡。这些研究确定了在缺乏或表达PR-A的同基因ER阳性细胞中受紫杉烷调控的基因。我们发现，unliganded PR-A改变了紫杉烷控制的基因表达模式，特别是多个基因参与纺锤体组装检查点，一组蛋白质，确保微管在有丝分裂过程中正确附着到动粒。重要的是，紫杉烷和未配体PR以相反的方向调节许多这些基因。因此，PR的存在加剧了有丝分裂滑移，导致体外和异种移植肿瘤中多核细胞数量增加。我们描述了一个简单的新的检测评估石蜡切片多核。我们推测，而不是诱导细胞死亡，unliganded PR利用多核化，以促进细胞的生存紫杉烷治疗。这可以用antibacteriostin来预防。
Whether the presence of steroid receptors in luminal breast cancers renders them resistant to taxanes remains uncertain. Here we assess the role of progesterone receptors (PR) on taxane-induced cell death. We previously showed that estrogen receptor (ER)-positive human breast cancer cells that inducibly express PR-A or PR-B isoforms were protected from taxane-stimulated apoptosis when compared to the identical cells lacking PR. Surprisingly, PR-dependent protection occurred in the absence of progesterone, demonstrating that the unliganded receptors were biologically active. The present studies demonstrate that unliganded PR, focused on PR-A, protect breast cancer cells from taxane-stimulated apoptosis. The studies identify genes regulated by taxanes in isogenic ER-positive cells that either lack or express PR-A. We show that unliganded PR-A alters the gene expression pattern controlled by taxanes, especially multiple genes involved in the spindle assembly checkpoint, a group of proteins that insure proper attachment of microtubules to kinetochores during mitosis. Importantly, taxanes and unliganded PR regulate many of these genes in opposite directions. As a result, mitotic slippage is exacerbated by the presence of PR, leading to an increase in the number of multinucleated cells both in vitro and in xenograft tumors. We describe a simple new assay for assessing multinucleation in paraffin sections. We speculate that rather than inducing cell death, unliganded PR exploits multinucleation to promote cell survival from taxane therapy. This can be prevented with antiprogestin.
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影响因子：
8
作者：
Makarovskiy, AN;Siryaporn, E;Akerley, W
通讯作者：
Akerley, W
影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
8
作者：
Hernandez-Vargas, H.;Palacios, J.;Moreno-Bueno, G.
通讯作者：
Moreno-Bueno, G.
影响因子：
3.3
作者：
Keyes, Brice E.;Yelhnan, Christopher M.;Burke, Daniel J.
通讯作者：
Burke, Daniel J.
影响因子：
45.3
作者：
Henderson, IC;Berry, DA;Norton, L
通讯作者：
Norton, L