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

• Published in: Nature (London) Vol. 573; no. 7774; pp. 439 - 444
• Main Authors: Padmanaban, Veena, Krol, Ilona, Suhail, Yasir, Szczerba, Barbara M., Aceto, Nicola, Bader, Joel S., Ewald, Andrew J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2019; Nature Publishing Group
• Subjects: 14/19; 14/63; 38; 38/91; 631/67/1347; 631/67/322; Analysis; Animal models; Animals; Antigens, CD - metabolism; Apoptosis; Bioinformatics; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins; Cadherins - metabolism; Carcinoma; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; Cell adhesion; Cell number; Cell proliferation; Cell survival; Collagen; Detachment; E-cadherin; Female; Genetic aspects; Genomes; Growth factors; Humanities and Social Sciences; Humans; Invasiveness; Letter; Metastases; Metastasis; Mice; multidisciplinary; Neoplasm Invasiveness; Neoplasm Metastasis; Organs; Oxidative stress; Oxygen; Patient outcomes; Prostate; Reactive oxygen species; Receptors, Transforming Growth Factor beta - metabolism; Science; Science (multidisciplinary); Signal transduction; Signaling; Smad2 protein; Survival; Survival factor; Transcription; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumors; United States; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1526-3

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-cadherin
1
,
2
, on the basis of inverse correlations between in vitro migration and E-cadherin levels
3
. However, this hypothesis is inconsistent with the observation that most breast cancers are invasive ductal carcinomas and express E-cadherin in primary tumours and metastases
4
. 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.
Although E-cadherin loss promotes tumour-cell invasion in mouse and human models of invasive ductal carcinoma, E-cadherin expression prevents oxidative-stress-mediated apoptosis during detachment and is essential for metastasis.