Influence of oestradiol and tamoxifen on oestrogen receptors-α and -β protein degradation and non-genomic signalling pathways in uterine and breast carcinoma cells
Influence of oestradiol and tamoxifen on oestrogen receptors-α and -β protein degradation and non-genomic signalling pathways in uterine and breast carcinoma cells
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DOI：
10.1677/jme.1.01784
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
White, INH
中科院分区：
文献类型：
--
作者：
Horner-Glister, E;Maleki-Dizaji, M;White, INH
他莫昔芬在乳房中作为雌激素拮抗剂减少细胞增殖，但在子宫中作为雌激素激动剂导致细胞增殖增加。他莫昔芬通过雌激素受体（ER α或ER β）发挥其组织特异性作用。这两种er的水平和功能影响靶组织对雌激素和他莫昔芬的反应。我们使用western blotting和RT-PCR检测了乳腺和子宫细胞系ER稳定性的控制。在MCF-7乳腺源性细胞中，雌激素受体α和雌激素受体β蛋白响应雌二醇通过蛋白酶体途径迅速降解；相反，他莫昔芬稳定了这两种受体。在Ishikawa子宫来源的细胞中，雌二醇和他莫昔芬稳定了ERa，但通过蛋白酶体途径导致ER β的降解。进一步的研究表明，雌二醇诱导MCF-7细胞中非基因组ER α /Akt信号通路的激活。我们已经证明，在没有活性蛋白酶体途径的情况下，雌二醇治疗后石川细胞中的Erk信号通路被激活，因此ER β水平增加。总之，我们的数据表明，他莫昔芬或雌二醇控制ER亚型的稳定性，转录途径的非基因组激活是细胞特异性的。
Tamoxifen acts as an oestrogen antagonist in the breast reducing cell proliferation, but in the uterus as an oestrogen agonist resulting in increased cell proliferation. Tamoxifen exerts its tissue-specific effects through the oestrogen receptors (ER alpha or ER beta). The levels and functions of the two ERs affect the response of the target tissue to oestrogen and tamoxifen. We examined the control of ER stability in breast and uterine cell lines using western blotting and RT-PCR. In MCF-7 breast-derived cells, ER alpha and ER beta proteins were rapidly degraded via the proteasome pathway in response to oestradiol; conversely tamoxifen stabilised both receptors. In Ishikawa uterine-derived cells, oestradiol and tamoxifen stabilised ERa but led to degradation of ER beta by the proteasome pathway. Further investigations showed that oestradiol induced activation of the non-genomic ER alpha/Akt signalling pathway in MCF-7 cells. We have demonstrated that the alternative Erk signalling pathway is activated in Ishikawa cells following oestradiol treatment in the absence of an active proteasome pathway and therefore increased levels of ER beta. In conclusion, our data have demonstrated tamoxifen or oestradiol control of ER subtype stability and that non-genomic activation of transcription pathways is cell specific.