TY - JOUR
T1 - A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior
AU - Schiano Lomoriello, Irene
AU - Giangreco, Giovanni
AU - Iavarone, Claudia
AU - Tordonato, Chiara
AU - Caldieri, Giusi
AU - Serio, Gaetana
AU - Confalonieri, Stefano
AU - Freddi, Stefano
AU - Bianchi, Fabrizio
AU - Pirroni, Stefania
AU - Bertalot, Giovanni
AU - Viale, Giuseppe
AU - Disalvatore, Davide
AU - Tosoni, Daniela
AU - Malabarba, Maria Grazia
AU - Disanza, Andrea
AU - Scita, Giorgio
AU - Pece, Salvatore
AU - Pilcher, Brian K.
AU - Vecchi, Manuela
AU - Sigismund, Sara
AU - Di Fiore, Pier Paolo
N1 - Funding Information:
We thank Rosalind Gunby for critically reading the manuscript; Chiara Luise, Giovanna Jodice, and Barbara Giulini for technical assistance; Marilena Bicchieri for help with the mammosphere assay; Alberto Gobbi, Manuela Capillo, and the Mouse facility (Cogen-tech Società Benefit Srl, Milan) for mice handling; Tom Kirchhausen for reagents and suggestions. The results shown in Fig. 1b are in part based upon the data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC - IG 18988, IG 23060 to P.P.D.F. and MCO 10.000; IG 18621, IG 22821 and MultiUnit −5 per Mille-22759 to GS; IG 11904, IG 15538, and MCO 10.000 to S.P.); the Italian Ministry of University and Scientific Research (MIUR) to P.P.D.F. (Prot. 2015XS92CC); the Italian Ministry of Health to D.T. (RF-2013-02358446); the Worldwide Cancer Research (16-1245) to S.S.; the European Research Council (Advanced-ERC − 268836) to G.S.; the Cariplo Foundation (2008.2448 to M.V.; 2011-0596 to A.D.). G.G., I.S.L., and C.T. were supported by an AIRC fellowship. This work was also partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-16836-y
DO - 10.1038/s41467-020-16836-y
M3 - Article
C2 - 32541686
AN - SCOPUS:85086602038
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3020
ER -