Estradiol-induced regression in T47D:A18/PKCalpha tumors requires the estrogen receptor and interaction with the extracellular matrix.
Estradiol-induced regression in T47D:A18/PKCalpha tumors requires the estrogen receptor and interaction with the extracellular matrix.
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雌二醇诱导的 T47D:A18/PKCα 肿瘤消退需要雌激素受体以及与细胞外基质的相互作用。
DOI：
10.1158/1541-7786.mcr-08-0415
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Tonetti,DebraA
中科院分区：
文献类型：
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作者：
Zhang,Yiyun;Zhao,Huiping;Asztalos,Szilard;Chisamore,Michael;Sitabkhan,Yasmin;Tonetti,DebraA
一些乳腺癌肿瘤模型通过细胞凋亡来响应雌二醇 (E2)，这是临床乳腺癌中已知的一种现象。在应用他莫昔芬作为内分泌治疗之前，大剂量E2或二乙烯雌醇治疗已被成功使用，尽管存在不利的副作用。现在人们认识到这种方法可能是一种潜在的内分泌治疗选择。我们在 T47D:A18/PKCα 肿瘤模型中探索了 E2 诱导的肿瘤消退机制，该模型表现出自主生长、他莫昔芬耐药性和 E2 诱导的肿瘤消退。氟维司群是一种选择性雌激素受体 (ER) 下调剂，在肿瘤形成之前或之后给药，可分别防止 T47D:A18/PKCα E2 诱导的肿瘤生长抑制和消退。有趣的是，E2 诱导的生长抑制仅在体内或当细胞在基质胶中生长时观察到，而不是在二维组织培养物中观察到，这表明需要细胞外基质。肿瘤消退伴随着促凋亡 FasL/FasL 配体蛋白表达的增加和促存活 Akt 通路的下调。 E2 对 Matrigel 中集落形成的抑制伴随着 FasL 表达的增加，并且短发夹 RNA 敲低部分逆转了集落形成抑制。 pS2、PR、转化生长因子-α、C3 和组织蛋白酶 D 的经典雌激素响应元件调节转录与 E2 的抑制作用无关。膜不可渗透的 E2-BSA 缀合物能够介导生长抑制，表明质膜 ER 参与其中。我们得出结论，E2 诱导的 T47D:A18/PKCα 肿瘤消退需要 ER-α、细胞外基质、FasL/FasL 配体和 Akt 通路的参与，从而有机会探索新的预测标记和治疗靶点。 （摩尔癌症研究 2009；7(4)：498–510）
Several breast cancer tumor models respond to estradiol (E2) by undergoing apoptosis, a phenomenon known to occur in clinical breast cancer. Before the application of tamoxifen as an endocrine therapy, high-dose E2or diethystilbesterol treatment was successfully used, albeit with unfavorable side effects. It is now recognized that such an approach may be a potential endocrine therapy option. We have explored the mechanism of E2-induced tumor regression in our T47D:A18/PKCα tumor model that exhibits autonomous growth, tamoxifen resistance, and E2-induced tumor regression. Fulvestrant, a selective estrogen receptor (ER) down-regulator, prevents T47D:A18/PKCα E2-induced tumor growth inhibition and regression when given before or after tumor establishment, respectively. Interestingly, E2-induced growth inhibition is only observedin vivoor when cells are grown in Matrigel but not in two-dimensional tissue culture, suggesting the requirement of the extracellular matrix. Tumor regression is accompanied by increased expression of the proapoptotic FasL/FasL ligand proteins and down-regulation of the prosurvival Akt pathway. Inhibition of colony formation in Matrigel by E2is accompanied by increased expression of FasL and short hairpin RNA knockdown partially reverses colony formation inhibition. Classic estrogen-responsive element-regulated transcription of pS2, PR, transforming growth factor-α, C3, and cathepsin D is independent of the inhibitory effects of E2. A membrane-impermeable E2-BSA conjugate is capable of mediating growth inhibition, suggesting the involvement of a plasma membrane ER. We conclude that E2-induced T47D:A18/PKCα tumor regression requires participation of ER-α, the extracellular matrix, FasL/FasL ligand, and Akt pathways, allowing the opportunity to explore new predictive markers and therapeutic targets. (Mol Cancer Res 2009;7(4):498–510)