Specific N-Cadherin-Dependent Pathways Drive Human Breast Cancer Dormancy in Bone Marrow

The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by formation of cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells (BCCs) show preference for bone marrow (BM), resulting in poor prognosis. CSCs utilize connexin 43 (Cx43) to form gap junctional intercellular communication (GJIC) with BM niche cells, fibroblasts and mesenchymal stem cells (MSCs). However, Cx43 is an unlikely target to reverse BC dormancy due to its role as hematopoietic regulator. We found N-cadherin (CDH2) and its associated pathways as potential drug targets. CDH2, highly expressed in CSCs, interacts intracellularly with Cx43, co-localizes with Cx43 in BCCs within BM biopsies of patients, and is required for Cx43-mediated GJIC with BM niche cells. Notably, CDH2-associated γ-secretase and pro-apoptotic pathways maintained BC dormancy. We thereby propose these pathways as potential pharmacological targets to prevent dormancy and chemosensitize resistant CSCs.