E-cadherin is required for metastasis in multiple models of breast cancer

Veena Padmanaban, Ilona Krol, Yasir Suhail, Barbara M. Szczerba, Nicola Aceto, Joel S. Bader and Andrew J. Ewald ()
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Veena Padmanaban: Johns Hopkins University
Ilona Krol: University of Basel and University Hospital Basel
Yasir Suhail: Johns Hopkins University
Barbara M. Szczerba: University of Basel and University Hospital Basel
Nicola Aceto: University of Basel and University Hospital Basel
Joel S. Bader: Johns Hopkins University
Andrew J. Ewald: Johns Hopkins University

Nature, 2019, vol. 573, issue 7774, 439-444

Abstract: Abstract Metastasis is the major driver of death in patients with cancer. Invasion of surrounding tissues and metastasis have been proposed to initiate following loss of the intercellular adhesion protein, E-cadherin1,2, on the basis of inverse correlations between in vitro migration and E-cadherin levels3. However, this hypothesis is inconsistent with the observation that most breast cancers are invasive ductal carcinomas and express E-cadherin in primary tumours and metastases4. To resolve this discrepancy, we tested the genetic requirement for E-cadherin in metastasis using mouse and human models of both luminal and basal invasive ductal carcinomas. Here we show that E-cadherin promotes metastasis in diverse models of invasive ductal carcinomas. While loss of E-cadherin increased invasion, it also reduced cancer cell proliferation and survival, circulating tumour cell number, seeding of cancer cells in distant organs and metastasis outgrowth. Transcriptionally, loss of E-cadherin was associated with upregulation of genes involved in transforming growth factor-β (TGFβ), reactive oxygen species and apoptosis signalling pathways. At the cellular level, disseminating E-cadherin-negative cells exhibited nuclear enrichment of SMAD2/3, oxidative stress and increased apoptosis. Colony formation of E-cadherin-negative cells was rescued by inhibition of TGFβ-receptor signalling, reactive oxygen accumulation or apoptosis. Our results reveal that E-cadherin acts as a survival factor in invasive ductal carcinomas during the detachment, systemic dissemination and seeding phases of metastasis by limiting reactive oxygen-mediated apoptosis. Identifying molecular strategies to inhibit E-cadherin-mediated survival in metastatic breast cancer cells may have potential as a therapeutic approach for breast cancer.

Date: 2019
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DOI: 10.1038/s41586-019-1526-3

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