Skip to Content
Merck
  • E-cadherin is required for metastasis in multiple models of breast cancer.

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

Nature (2019-09-06)
Veena Padmanaban, Ilona Krol, Yasir Suhail, Barbara M Szczerba, Nicola Aceto, Joel S Bader, Andrew J Ewald
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Tirofiban, ≥98.5% (HPLC)
Sigma-Aldrich
Cholera Toxin from Vibrio cholerae, ≥90% (SDS-PAGE), lyophilized powder
Sigma-Aldrich
Sodium dodecyl sulfate, BioReagent, suitable for electrophoresis, for molecular biology, ≥98.5% (GC)
Supelco
Bupivacaine hydrochloride monohydrate, analytical standard, for drug analysis
Sigma-Aldrich
Insulin solution human, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
Bovine Serum Albumin solution, 30% in DPBS, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
hEGF, EGF, recombinant, expressed in E. coli, lyophilized powder, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Collagenase from Clostridium histolyticum, suitable for release of rat epididymal adipocytes and hepatocytes (for methodology see Type II and Type IV), Type VIII, 0.5-5.0 FALGPA units/mg solid, ≥125 CDU/mg solid
Sigma-Aldrich
hBFGF, FGF-Basic, recombinant, expressed in E. coli, suitable for cell culture
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - high glucose, With 4500 mg/L glucose, sodium pyruvate, and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Penicillin-Streptomycin, Solution stabilized, with 10,000 units penicillin and 10 mg streptomycin/mL, 0.1 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Sodium dodecyl sulfate, BioReagent, suitable for electrophoresis, for molecular biology, ≥98.5% (GC), free-flowing, Redi-Dri
Sigma-Aldrich
(Z)-4-Hydroxytamoxifen, ≥98% Z isomer
Sigma-Aldrich
N-Acetyl-L-cysteine, Sigma Grade, ≥99% (TLC), powder
Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, Standardized vial containing 2,000 Kunitz units of DNase I (D4527), vial of ≥0.25 mg total protein
Sigma-Aldrich
Tamoxifen, ≥99%
Sigma-Aldrich
Glycerol, for molecular biology, ≥99.0%
Sigma-Aldrich
Anti-Actin, N-terminal antibody produced in rabbit, ~0.5 mg/mL, affinity isolated antibody, buffered aqueous solution