Nature communications · 2020
A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Schiano Lomoriello Irene, Giangreco Giovanni, Iavarone Claudia, Tordonato Chiara, Caldieri Giusi, Serio Gaetana, Confalonieri Stefano, Freddi Stefano, Bianchi Fabrizio, Pirroni Stefania, Bertalot Giovanni, Viale Giuseppe, Disalvatore Davide, Tosoni Daniela, Malabarba Maria Grazia, Disanza Andrea, Scita Giorgio, Pece Salvatore, Pilcher Brian K, Vecchi Manuela, Sigismund Sara, Di Fiore Pier Paolo
Аннотация
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.