Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer.
Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer.
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DOI：
10.18632/oncotarget.7533
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发表时间：
2016-03-29
期刊：
影响因子：
--
通讯作者：
Das GM
中科院分区：
文献类型：
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作者：
Swetzig WM;Wang J;Das GM
MDM2和MDM4是异二聚体、非冗余的癌蛋白，可以有效地抑制P53抑癌蛋白。在体外和体内模型中，MDM2和MDM4也可以增强乳腺癌细胞的致瘤性，并且在原发人类乳腺癌中过表达。以往的研究表明，雌激素受体α(ERα/ESR1)是mdm2表达的调节因子，也是mdm2和p53相互作用的蛋白。然而，ERα和MDM4之间的类似串扰尚未被研究。此外，介导MDM4在人类乳腺癌中过表达的信号通路仍有待阐明。利用癌症基因组图谱，我们分析了乳腺浸润性癌患者队列中ERα状态与mdm4和mdm2表达的相关性。我们报告mdm4和mdm2在A/B亚型原发乳腺癌中的表达升高，并与ERα阳性疾病相关，与P53突变状态无关。此外，在细胞培养模型中，ERα通过不依赖于P53的机制正向调节mdm4和mdm2的表达，这些作用可以被临床相关的内分泌治疗药物fulvestrant和Tamoxifen所阻断。此外，ERα还能正向调节P53的表达。最后，我们报道了内源性mdm4负性调节ERα的表达，并与ERα在乳腺癌细胞系和原代人乳腺肿瘤组织中形成蛋白质复合体。这表明乳腺癌细胞中ER、α和mdm4的表达之间存在直接的信号串扰和负反馈环。总之，这些新的发现暗示ERα是人类乳腺癌中p53-mdm2-mdm4信号轴的中心组成部分。
MDM2 and MDM4 are heterodimeric, non-redundant oncoproteins that potently inhibit the p53 tumor suppressor protein. MDM2 and MDM4 also enhance the tumorigenicity of breast cancer cells in in vitro and in vivo models and are overexpressed in primary human breast cancers. Prior studies have characterized Estrogen Receptor Alpha (ERα/ESR1) as a regulator of MDM2 expression and an MDM2- and p53-interacting protein. However, similar crosstalk between ERα and MDM4 has not been investigated. Moreover, signaling pathways that mediate the overexpression of MDM4 in human breast cancer remain to be elucidated. Using the Cancer Genome Atlas (TCGA) breast invasive carcinoma patient cohort, we have analyzed correlations between ERα status and MDM4 and MDM2 expression in primary, treatment-naïve, invasive breast carcinoma samples. We report that the expression of MDM4 and MDM2 is elevated in primary human breast cancers of luminal A/B subtypes and associates with ERα-positive disease, independently of p53 mutation status. Furthermore, in cell culture models, ERα positively regulates MDM4 and MDM2 expression via p53-independent mechanisms, and these effects can be blocked by the clinically-relevant endocrine therapies fulvestrant and tamoxifen. Additionally, ERα also positively regulates p53 expression. Lastly, we report that endogenous MDM4 negatively regulates ERα expression and forms a protein complex with ERα in breast cancer cell lines and primary human breast tumor tissue. This suggests direct signaling crosstalk and negative feedback loops between ERα and MDM4 expression in breast cancer cells. Collectively, these novel findings implicate ERα as a central component of the p53-MDM2-MDM4 signaling axis in human breast cancer.