@article{186241,
  keywords = {Animals, signal transduction, Mice, Female, Neoplasm Proteins, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Vesicular Transport, Mammary Neoplasms, Animal, Ubiquitination},
  author = {Kai Song and Xiaofeng Cai and Yunzhou Dong and Hao Wu and Yong Wei and Uma Shankavaram and Kui Cui and Yang Lee and Bo Zhu and Sudarshan Bhattacharjee and Beibei Wang and Kun Zhang and Aiyun Wen and Scott Wong and Lili Yu and Lijun Xia and Alana Welm and Diane Bielenberg and Kevin Camphausen and Yibin Kang and Hong Chen},
  title = {Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development},
  abstract = {<p>Estrogen receptor-negative (ER-negative) breast cancer is thought to be more malignant and devastating than ER-positive breast cancer. ER-negative breast cancer exhibits elevated NF-κB activity, but how this abnormally high NF-κB activity is maintained is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its ubiquitin-interacting motif and bound LUBAC{\textquoteright}s bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling and provide an important perspective into ER-negative breast cancer treatment.</p>
},
  year = {2021},
  journal = {J Clin Invest},
  volume = {131},
  month = {01/2021},
  issn = {1558-8238},
  doi = {10.1172/JCI129374},
  language = {eng},
}