Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells (Retracted Article. See vol 107, pg 22360, 2010)
Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells (Retracted Article. See vol 107, pg 22360, 2010)
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DOI：
10.1073/pnas.0809516106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Andersson, Tommy
中科院分区：
文献类型：
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作者：
Ford, Caroline E.;Ekstrom, Elin J.;Andersson, Tommy
三分之一的乳腺癌是雌激素受体α (ER α)阴性，总体预后较差，并且对目前可用的内分泌治疗反应不佳。因此需要新的治疗策略。Wnt-5a的缺失先前在临床乳腺癌样本中与ER α的缺失相关，我们试图进一步研究这种关联。本研究使用了三种缺乏ER α和Wnt-5a表达的乳腺癌细胞系（MDA-MB-231、MDA-MB-468和4T1）和一种同时表达这两种蛋白的乳腺癌细胞系（T47D）。重组Wnt-5a蛋白或具有Wnt-5a信号特性的Wnt-5a衍生的六肽（Foxy-5）刺激ER α阴性细胞系产生Wnt-5a信号。重组Wnt-5a或Foxy-5处理后，ER α在mRNA和蛋白水平上均恢复表达。这种表达的恢复与ER α启动子甲基化的减少同时发生。上调的ER α可以激活，启动孕激素受体和pS2的转录，并激活雌激素反应元件报告结构。值得注意的是，重新表达ER α的乳腺癌细胞对选择性雌激素受体调节剂他莫昔芬治疗有反应，通过诱导凋亡和细胞生长抑制来测量。最后，Foxy-5在ER α阴性乳腺癌体内模型中也增加了ER α的表达。这是Wnt-5a信号通路在ER α阴性乳腺癌细胞中重建ER α表达的第一个证据。我们的数据表明Foxy-5和他莫昔芬联合治疗应该被认为是ER α阴性乳腺癌患者未来治疗的可能性。
One third of all breast cancers are estrogen receptor alpha (ER alpha) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ER alpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ER alpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ER alpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ER alpha expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ER alpha promoter. Up-regulated ER alpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ER alpha responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ER alpha expression in an in vivo model of ER alpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ER alpha expression in ER alpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ER alpha-negative breast cancer patients.