1. A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior.
- Author
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Schiano Lomoriello I, Giangreco G, Iavarone C, Tordonato C, Caldieri G, Serio G, Confalonieri S, Freddi S, Bianchi F, Pirroni S, Bertalot G, Viale G, Disalvatore D, Tosoni D, Malabarba MG, Disanza A, Scita G, Pece S, Pilcher BK, Vecchi M, Sigismund S, and Di Fiore PP
- Subjects
- Adaptor Proteins, Vesicular Transport genetics, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cadherins genetics, Cadherins metabolism, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Signal Transduction, Transcription Factor 4 genetics, Transcription Factor 4 metabolism, Transforming Growth Factor beta metabolism, beta Catenin genetics, beta Catenin metabolism, Adaptor Proteins, Vesicular Transport metabolism, Breast Neoplasms physiopathology, Endocytosis
- 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.
- Published
- 2020
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