A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior
Open Access
- 15 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-20
- https://doi.org/10.1038/s41467-020-16836-y
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 beta-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGF beta-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 TGF beta-dependent regulatory loops conferring cellular plasticity and invasive behavior.This publication has 72 references indexed in Scilit:
- The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 2012
- Membrane Fission Is Promoted by Insertion of Amphipathic Helices and Is Restricted by Crescent BAR DomainsCell, 2012
- Endocytic Internalization Routes Required for Delta/Notch SignalingCurrent Biology, 2010
- Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumorOncogene, 2009
- Clathrin-Mediated Internalization Is Essential for Sustained EGFR Signaling but Dispensable for DegradationDevelopmental Cell, 2008
- The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsCell, 2008
- NUMB controls p53 tumour suppressor activityNature, 2008
- A single lentiviral vector platform for microRNA-based conditional RNA interference and coordinated transgene expressionProceedings of the National Academy of Sciences of the United States of America, 2006
- A Randomized Comparison of Sentinel-Node Biopsy with Routine Axillary Dissection in Breast CancerThe New England Journal of Medicine, 2003
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2003