A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior

Irene Schiano Lomoriello, Giovanni Giangreco, Claudia Iavarone, Chiara Tordonato, Giusi Caldieri, Gaetana Serio, Stefano Confalonieri, Stefano Freddi, Fabrizio Bianchi, Stefania Pirroni, Giovanni Bertalot, Giuseppe Viale, Davide Disalvatore, Daniela Tosoni, Maria Grazia Malabarba, Andrea Disanza, Giorgio Scita, Salvatore Pece, Brian K. Pilcher, Manuela VecchiSara Sigismund, Pier Paolo Di Fiore

Research output: Contribution to journalArticlepeer-review

Abstract

The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.

Original languageEnglish
Article number3020
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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