Gao Chong, Xiao Gu, Bargonetti Jill
The Department of Biological Sciences at Hunter College, Belfer Building, City University of New York, New York, NY, USA.
The Graduate Center Biology Program of City University of New York, New York, NY, USA.
Oncotarget. 2019 Aug 20;10(49):5007-5010. doi: 10.18632/oncotarget.27134.
MDMX (MDM4) is emerging as an important breast cancer (BC) biomarker, and oncoprotein, that can be targeted in combination with its well-known family member MDM2. While MDM2 has previously been implicated in driving BC metastasis, information about the role of MDMX in driving circulating tumor cells (CTCs) and BC metastasis is lacking. BCs often have alterations of MDM2, MDMX, and mutant p53 (mtp53). Therefore, the role of MDM2 and MDMX in the context of mtp53 in BCs requires further clarification. Our group has recently reported that triple negative breast cancer (TNBC) metastasis is dependent on both MDM2 and MDMX, and depleting MDM2 results in increased MDMX, but depleting MDMX does not cause an increase in MDM2. In the context of human TNBC expressing mtp53 in an orthotopic mouse model the down-regulation of MDMX virtually cleared CTCs from the blood. Contemplations, using the available literature, suggest that disrupting the stability and/or function of MDMX protein (and its downstream targets), in the context of mtp53 expressing BCs, might be beneficial for patient survival. It remains to be determined if blocking mtp53-MDMX pathways can inhibit early stage TNBC and eliminate CTCs that have the potential to form metastatic lesions.
MDMX（MDM4）正逐渐成为一种重要的乳腺癌（BC）生物标志物和癌蛋白，可与它广为人知的家族成员MDM2联合作为靶点。虽然此前已有研究表明MDM2会促使BC转移，但关于MDMX在驱动循环肿瘤细胞（CTC）和BC转移中的作用尚缺乏相关信息。BC常常存在MDM2、MDMX和突变型p53（mtp53）的改变。因此，在BC中mtp53背景下MDM2和MDMX的作用需要进一步阐明。我们团队最近报告称，三阴性乳腺癌（TNBC）转移依赖于MDM2和MDMX两者，敲除MDM2会导致MDMX增加，但敲除MDMX不会使MDM2增加。在原位小鼠模型中表达mtp53的人TNBC背景下，下调MDMX实际上可清除血液中的CTC。根据现有文献推测，在表达mtp53的BC背景下，破坏MDMX蛋白（及其下游靶点）的稳定性和/或功能可能对患者生存有益。阻断mtp53-MDMX通路是否能抑制早期TNBC并消除有形成转移病灶潜力的CTC，仍有待确定。
