很多鸟嘌呤核苷酸交换因子（GEFs）如上皮细胞转化因子ECT2，可通过激活不同的GTP酶驱动肿瘤的发生发展。但是，这些因子是否可以不依赖于GEF活性在肿瘤发生发展中发挥作用尚不清楚。我们以ECT2为研究对象，初步发现：1）乳腺癌中高表达的ECT2不依赖GEF活性促进乳腺癌细胞存活；2）ECT2与蛋白质去泛素化酶USP7相互作用；3）ECT2可调节USP7底物蛋白如MDM2等的稳定性；4）USP7在蛋白水平稳定ECT2。根据以上结果和USP7的癌基因活性，我们猜想ECT2和USP7可能形成正反馈环路，且不依赖于GEF活性促进乳腺癌的发生发展。然而ECT2如何调节USP7底物蛋白的稳定性，以及ECT2/USP7环路如何影响乳腺癌细胞存活等科学问题还有待深入探索。以上问题的阐明，有助于我们从不同的视角理解GEF因子发挥作用的分子机制，加深我们对USP7调节机理的认识，为乳腺癌治疗提供潜在的靶点。

A number of guanine nucleotide exchange factors (GEFs) including cell transforming factor ECT2 are believed to drive carcinogenesis through activating distinct oncogenic GTPases. Yet, whether GEF-independent activity of these factors also plays a role in tumorigenesis remains unclear. In this study, we found that ECT2 is highly expressed in different subtypes of breast cancer and high expression of ECT2 significantly correlates with worse survivals of breast cancer patients. Surprisingly, we demonstrated that GEF activity-deficient ECT2 is able to alleviate ECT2 depletion associated growth defects in breast cancer cells. Mass spectrometry analysis of ECT2 containing protein complex revealed that ECT2 is physically associated with ubiquitin-specific protease USP7. Furthermore, we found that ECT2 depletion resulted in markedly downregulation of several USP7 substrates including PHF8, RNF168 and MDM2. Reciprocally, we demonstrated that USP7 is responsible for ECT2 stabilization. According to these preliminary data and the fact that USP7 is an oncogenic protein, we propose that ECT2 and USP7 possibly shape a feedforward circuit to control the expression of each other and the reciprocal stabilization of these proteins may contribute to breast carcinogenesis. However, the molecular mechanism of ECT2-promoted USP7 substrates’ stabilization remains to be investigated. Also, we will identify how the positive feedback loop formed by ECT2 and USP7, if it is true, promotes breast cancer cell survival. Our study points to a GEF-independent role for ECT2 in breast cancer, and will provide a molecular insight for the reciprocal regulation of ECT2 and USP7, supporting the pursuit of ECT2/USP7 as potential targets for breast cancer intervention. We believe that our study will contribute to the advancement of our understanding of the molecular as well as biological function of ECT2 and USP7 in specific and to our understanding of protein deubiquitination and breast carcinogenesis in general.