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.
A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior / I. Schiano Lomoriello, G. Giangreco, C. Iavarone, C. Tordonato, G. Caldieri, G. Serio, S. Confalonieri, S. Freddi, F. Bianchi, S. Pirroni, G. Bertalot, G. Viale, D. Disalvatore, D. Tosoni, M.G. Malabarba, A. Disanza, G. Scita, S. Pece, B.K. Pilcher, M. Vecchi, S. Sigismund, P.P. Di Fiore. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020 Dec 01).
|Titolo:||A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior|
SIGISMUND, SARA LUCIA GIUSTINA (Penultimo) (Corresponding)
DI FIORE, PIER PAOLO (Ultimo) (Corresponding)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/08 - Anatomia Patologica
Settore BIO/13 - Biologia Applicata
|Progetto:||Biological modifiers of HER2 in cancer: from genomic landscape and mechanistic signaling to therapeutic efficacy of HER2 inhibitors|
|Data di pubblicazione:||1-dic-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41467-020-16836-y|
|Appare nelle tipologie:||01 - Articolo su periodico|