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 Vecchi, Sara Sigismund () and Pier Paolo Di Fiore ()
Additional contact information
Irene Schiano Lomoriello: IEO, Istituto Europeo di Oncologia IRCCS
Giovanni Giangreco: IEO, Istituto Europeo di Oncologia IRCCS
Claudia Iavarone: IEO, Istituto Europeo di Oncologia IRCCS
Chiara Tordonato: IEO, Istituto Europeo di Oncologia IRCCS
Giusi Caldieri: IEO, Istituto Europeo di Oncologia IRCCS
Gaetana Serio: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Stefano Confalonieri: IEO, Istituto Europeo di Oncologia IRCCS
Stefano Freddi: IEO, Istituto Europeo di Oncologia IRCCS
Fabrizio Bianchi: IEO, Istituto Europeo di Oncologia IRCCS
Stefania Pirroni: IEO, Istituto Europeo di Oncologia IRCCS
Giovanni Bertalot: IEO, Istituto Europeo di Oncologia IRCCS
Giuseppe Viale: IEO, Istituto Europeo di Oncologia IRCCS
Davide Disalvatore: IEO, Istituto Europeo di Oncologia IRCCS
Daniela Tosoni: IEO, Istituto Europeo di Oncologia IRCCS
Maria Grazia Malabarba: IEO, Istituto Europeo di Oncologia IRCCS
Andrea Disanza: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Giorgio Scita: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Salvatore Pece: IEO, Istituto Europeo di Oncologia IRCCS
Brian K. Pilcher: UTSW Medical Center, Department of Cell Biology
Manuela Vecchi: IEO, Istituto Europeo di Oncologia IRCCS
Sara Sigismund: IEO, Istituto Europeo di Oncologia IRCCS
Pier Paolo Di Fiore: IEO, Istituto Europeo di Oncologia IRCCS

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16836-y

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