ALTERATION IN THE AGONIST/ANTAGONIST BALANCE OF ANTIESTROGENS BY ACTIVATION OF PROTEIN-KINASE A SIGNALING PATHWAYS IN BREAST-CANCER CELLS - ANTIESTROGEN SELECTIVITY AND PROMOTER DEPENDENCE
ALTERATION IN THE AGONIST/ANTAGONIST BALANCE OF ANTIESTROGENS BY ACTIVATION OF PROTEIN-KINASE A SIGNALING PATHWAYS IN BREAST-CANCER CELLS - ANTIESTROGEN SELECTIVITY AND PROMOTER DEPENDENCE
复制标题
DOI：
10.1210/me.8.3.296
复制
发表时间：
1994-03-01
影响因子：
--
通讯作者：
KATZENELLENBOGEN, BS
中科院分区：
文献类型：
--
作者：
FUJIMOTO, N;KATZENELLENBOGEN, BS
我们发现，刺激MCF-7人乳腺癌细胞中的蛋白激酶A（PKA）信号通路改变了他莫昔芬和相关抗雌激素的激动剂/拮抗剂活性;它激活或增强了它们的雌激素激动剂活性，并降低了它们拮抗雌二醇（E（2））作用的能力。在含有高水平内源性雌激素受体（ER）的MCF-7人乳腺癌细胞中，抗雌激素反式-羟基-他莫昔芬（TOT）不能刺激雌激素应答启动子-报告基因构建体雌激素应答元件（ERE）-TATA-氯霉素乙酰转移酶（CAT）、（ERE）（2）-TATA-CAT和pS2-CAT的转录。当细胞用异丁基甲基黄嘌呤加霍乱毒素处理时（其使细胞内cAMP增加约10倍），或用8-溴-cAMP，或用PKA催化亚基的表达载体转染，抗雌激素-ER复合物的转录活性现在增加到E（2）的20-75%的水平，并且TOT在拮抗E（2）对转录的刺激方面也变得不那么有效。虽然在三种启动子-报告基因构建体（包含一个简单的TATA启动子或一个更复杂的pS2启动子）中观察到了TOT的激动剂和拮抗剂活性的这种变化，但cAMP的升高并没有增强TOT或E（2）报告基因质粒ERE-胸苷激酶-CAT的转录。因此，这种现象是启动子特异性的。异丁基甲基黄嘌呤加霍乱毒素和PKA催化亚基对TOT和E（2）转录增强的最大刺激作用不是相加的，这与它们都通过刺激相同的信号转导途径起作用的假设一致。相比之下，cAMP和PKA催化亚基转染未能引起任何转录的更纯的抗雌激素ICI 164，384与任何四个启动子-报告结构测试。我们的研究结果表明，PKA信号通路的刺激激活了他莫昔芬样抗雌激素的激动剂活性，这可能部分解释了一些含ER的乳腺癌对他莫昔芬耐药的发展。他们还认为，使用像ICI 164，384这样的抗雌激素药物，在cAMP存在的情况下不能激活ER转录，可能证明对乳腺癌的长期抗雌激素治疗更有效。
We find that stimulation of the protein kinase A (PKA) signaling pathway in MCF-7 human breast cancer cells changes the agonist/antagonist activity of tamoxifen and related antiestrogens; it activates or enhances their estrogen agonist activity and reduces their ability to antagonize the effects of estradiol (E(2)). In MCF-7 human breast cancer cells which contain high levels of endogenous estrogen receptor (ER), the antiestrogen trans-hydroxy-tamoxifen (TOT) fails to stimulate transcription of the estrogen-responsive promoter-reporter constructs estrogen response element (ERE)-TATA-chloramphenicol acetyl transferase (CAT), (ERE)(2)-TATA-CAT, and pS2-CAT. However, when cells are treated with isobutyl methylxanthine plus cholera toxin (which increases intracellular cAMP approximately 10-fold), or with 8-bromo-cAMP, or are transfected with expression vectors for the PKA catalytic subunits, the transcriptional activity of the antiestrogen-ER complex is now increased, to levels 20-75% that of E(2), and TOT also becomes much less effective in antagonizing the stimulation of transcription by E(2). Although this alteration in the agonist and antagonist activity of TOT is observed with three promoter-reporter constructs, containing a simple TATA promoter or a more complex, pS2 promoter, elevation of cAMP did not enhance the transcription by either TOT or E(2) of the reporter plasmid ERE-thymidine kinase-CAT. Thus, this phenomenon is promoter specific. The maximal stimulatory effects of isobutylmethylxanthine plus cholera toxin and PKA catalytic subunits on TOT and E(2) transcriptional enhancement were not additive, consistent with the hypothesis that they are both acting via stimulation of the same signal transduction pathway. By contrast, cAMP and PKA catalytic subunit transfection failed to evoke any transcription by the more pure antiestrogen ICI164,384 with any of the four promoter-reporter constructs tested. Our findings, documenting that stimulation of the PKA signaling pathway activates the agonist activity of tamoxifen-like antiestrogens, may in part explain the development of tamoxifen resistance by some ER-containing breast cancers. They also suggest that the use of antiestrogens like ICI164,384, that fail to activate ER transcription in the presence of cAMP, may prove more effective for long-term antiestrogen therapy in breast cancer.