Reversal of the estrogen receptor-negative phenotype in breast cancer and restoration of antiestrogen response
Reversal of the estrogen receptor-negative phenotype in breast cancer and restoration of antiestrogen response
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DOI：
10.1158/1078-0432.ccr-07-0587
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发表时间：
2007-12-01
影响因子：
11.5
通讯作者：
El Ashry, Dorraya
中科院分区：
文献类型：
--
作者：
Bayliss, Jill;Hilger, Amy;El Ashry, Dorraya
目的：在乳腺癌中，雌激素受体α（ER）的存在意味着更好的预后和对抗雌激素治疗的反应。ER α的缺乏与表皮生长因子受体或c-erbB-2的过度表达相关。我们已经表明，丝裂原活化蛋白激酶（MAPK）的过度活化直接抑制ER α表达的可逆方式。在这项研究中，我们确定在已建立的ER α（-）乳腺癌细胞系和肿瘤中抑制MAPK是否会导致ER α的再表达，以及在这些ER α（-）肿瘤和细胞系中ER α的再表达是否可以恢复抗雌激素反应。本研究中使用了已建立的ER α（-）乳腺癌细胞系、ER α（-）乳腺肿瘤和从ER α（-）肿瘤中获得的肿瘤细胞培养物。通过MAPK/ERK激酶1/2抑制剂U 0126或通过易瑞沙或赫赛汀的上游抑制来实现对过度活跃的MAPK的抑制。使用ER α的Western印迹或逆转录-PCR来评估用U 0126处理的细胞中ER α的再表达。WST-1的生长测定，以评估这些cells.Results：ERa乳腺癌细胞系中的MAPK活性的抑制导致ER α的重新表达，通过靶向表皮生长因子受体或c-erbB-2的上游抑制同样有效。重要的是，这种重新表达的ER α现在可以在这些ER α（-）乳腺癌细胞系的一个子集中介导抗雌激素反应。用MAPK抑制剂处理ER α（-）肿瘤标本可恢复ER α mRNA，同样，在ER α（-）肿瘤的上皮细胞培养物中，MAPK抑制可恢复ER α蛋白和抗雌激素反应。这些数据显示了ER α（-）乳腺癌中ER α表达恢复和抗雌激素反应的可能性，并提示存在ER α（-）乳腺癌，将受益于MAPK抑制/激素联合治疗的乳腺癌患者。
Purpose: In breast cancer, the presence of estrogen receptor alpha (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ER alpha correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ER alpha expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ER alpha(-) breast cancer cell lines and tumors results in reexpression of ER alpha, and further, if reexpression of ER alpha in these ER alpha(-) tumors and cell lines could restore antiestrogen responses.Experimental Design: Established ER alpha(-) breast cancer cell lines, ER alpha(-) breast tumors, and tumor cell cultures obtained from ER alpha(-) tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ER alpha was used to assess the reexpression of ER alpha in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells.Results: Inhibition of MAPK activity in ERa breast cancer cell lines results in reexpression of ER alpha; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ER alpha can now mediate an antiestrogen response in a subset of these ER alpha(-) breast cancer cell lines. Treatment of ER alpha(-) tumor specimens with MAPK inhibitors results in restoration of ER alpha mRNA, and similarly in epithelial cultures from ER alpha(-) tumors, MAPK inhibition restores both ER alpha protein and antiestrogen response.Conclusions: These data show both the possibility of restoring ERa expression and antiestrogen responses in ER alpha(-) breast cancer and suggest that there exist ER alpha(-) breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.