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

Abstract

SUMMARYMetastasis is the major driver of cancer deaths and begins when cancer cells invade surrounding tissues. Invasion and metastasis have been proposed to initiate following loss of the intercellular adhesion protein, E-cadherin (E-cad)1,2, based upon inverse correlations between in vitro migration and E-cad levels3. This hypothesis is inconsistent, however, with the observation that most breast cancers are invasive ductal carcinomas (IDC) and express E-cad in primary tumors and metastases4. To resolve this discrepancy, we tested the genetic requirement for E-cad in metastasis using murine and human models of both luminal and basal IDC. Here we show that E-cad promotes metastasis in IDC. While loss of E-cad increased invasion, it also reduced cancer cell proliferation and survival, circulating tumor cell number, seeding of cancer cells in distant organs, and metastasis formation. Transcriptionally, loss of E-cad was associated with upregulation of TGFβ, reactive oxygen, and apoptosis signaling pathways. At the cellular level, disseminating E-cad-negative cells exhibited nuclear enrichment of SMAD2/3, oxidative stress, and elevated apoptosis rates. Colony formation of E-cad-negative cells was rescued by inhibition of TGFβ receptor signaling, reactive oxygen accumulation, or apoptosis. Our results reveal that E-cad acts as a survival factor in IDC during the detachment, systemic dissemination, and seeding phases of metastasis by limiting reactive oxygen-mediated apoptosis. Identifying molecular strategies to inhibit E-cad mediated survival in metastatic breast cancer cells could potentially be a new therapeutic approach for breast cancer.