Ets-2 and p160 proteins collaborate to regulate c-Myc in endocrine resistant breast cancer
Ets-2 and p160 proteins collaborate to regulate c-Myc in endocrine resistant breast cancer
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DOI：
10.1038/sj.onc.1210964
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发表时间：
2008-05-08
期刊：
影响因子：
8
通讯作者：
Young, L. S.
中科院分区：
文献类型：
--
作者：
Al-Azawi, D.;Mc Ilroy, M.;Young, L. S.
p160辅激活蛋白与内分泌抵抗之间的关系已被描述。尽管p160蛋白被认为主要与类固醇受体相互作用，但它也可以与非核受体转录因子相互作用，包括MAP激酶效应蛋白Ets。在这里，我们观察到，在对内分泌治疗有抗性和不敏感的乳腺癌细胞中，生长因子EGF诱导了Ets-2而不是Ets-1对癌基因myc的转录调节。发现Ets-2对myc的调控依赖于p160蛋白SRC-1和SRC-3。为了支持这些分子观察结果，在一组局部晚期乳腺癌患者中，转录因子Ets-2及其辅激活子SRC-1 （P < 0.01）与靶基因myc （P < 0.0001）之间存在很强的相关性。Ets-2、SRC-1和c-Myc的表达均与无病生存期降低相关（P < 0.001、P < 0.001和P = 0.002）。SRC-3与无病生存无相关性（P = 0.707）。SRC-1可以利用MAP激酶效应转录因子Ets-2调控致癌基因myc的产生。这些信号机制在类固醇耐药/非依赖性乳腺癌的发展中可能很重要。
Associations between p160 coactivator proteins and endocrine resistance have been described. Though thought to primarily interact with steroid receptors, the p160 proteins can also interact with non-nuclear receptor transcription factors including the MAP kinase effector proteins Ets. Here, we observed that in breast cancer cells resistant and insensitive to endocrine treatment, the growth factor EGF induced Ets-2 but not Ets-1 transcriptional regulation of the oncogene myc. Ets-2 regulation of myc was found to be reliant on the p160 proteins SRC-1 and SRC-3. In support of these molecular observations, strong associations were observed between the transcription factor, Ets-2 and its coactivator SRC-1 (P < 0.01) and the target gene myc (P < 0.0001) in a cohort of breast cancer patients with locally advanced disease. Expression of Ets-2, SRC-1 and c-Myc individually all associated with reduced disease-free survival (P < 0.001, P < 0.001 and P = 0.002 respectively). There was no association between SRC-3 and disease-free survival (P = 0.707). SRC-1 can utilize MAP kinase effector transcription factor Ets-2 to regulate the production of the oncogene myc. These signalling mechanisms maybe important in the development of steroid resistant/independent breast cancer.