Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Nishanth Belugali Nataraj, Ashish Noronha, Joo Sang Lee, Soma Ghosh, Harsha Raj Mohan Raju, Arunachalam Sekar, Binyamin Zuckerman, Moshit Lindzen, Emilio Tarcitano, Swati Srivastava, Michael Selitrennik, Ido Livneh, Diana Drago-Garcia, Oscar Rueda, Carlos Caldas, Sima Lev, Tamar Geiger, Aaron Ciechanover, Igor Ulitsky, Rony SegerEytan Ruppin, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.

Original languageEnglish
Article number110418
JournalCell Reports
Issue number8
StatePublished - 22 Feb 2022


  • TGF-β/SMAD
  • WNT/β-catenin
  • breast cancer
  • cancer hallmark
  • importin
  • metastasis
  • nuclear pore
  • nuclear transport
  • transcription factor


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