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A Self-Sustaining Endocytic-Based Loop Promotes Breast Cancer Plasticity Leading to Aggressiveness and Pro-Metastatic Behavior

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2020

Nat Commun. 2020 Jun 15;11(1):3020. doi: 10.1038/s41467-020-16836-y.

A Self-Sustaining Endocytic-Based Loop Promotes Breast Cancer Plasticity Leading to Aggressiveness and Pro-Metastatic Behavior

I Schiano Lomoriello;G Giangreco;C Lavarone;C Tordonato;G Caldieri;G Serio;S Cofalonieri;S Freddi;F Bianchi;S Pirroni;G Bertalot;G Viale;D Disalvatore;D Tosoni;MG Malabarba;A Disanza;G Scita;S Pece;BK Pilcher;M Vecchi;S Sigismund;PP di Fiore

IEO, Istituto Europeo di Oncologia IRCCS, Via Ripamonti 435, 20141, Milan, Italy. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139, Milan, Italy. Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-oncologia, Via Santa Sofia 9/1, 20122, Milan, Italy. Institute for Stem-cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Casa Sollievo della Sofferenza Hospital - IRCCS, San Giovanni Rotondo, (FG), Italy. Divisione di Anatomia e Istologia Patologica, Presidio San Giovanni Di Dio, Via Ospedale 46, Cagliari, Italy. UTSW Medical Center, Department of Cell Biology, Dallas, TX, USA. Critical Mass Scientific Strategy Consultants, Raleigh, NC, USA. Cogentech S.R.L. Benefit Corporation with a Sole Shareholder, Via Adamello 16, 20139, Milan, Italy.

Service type: Transgenic mice

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.

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