CDH2-microRNA Axis Provides Insights into Sustained Breast Cancer Dormancy in the Bone Marrow Niche

Abstract

Despite long-term remission of breast cancer (BC), cancer resurgence remains a clinical issue. This issue is mostly due to BC cells (BCCs) being able to survive in dormancy for decades. This is particularly relevant to the bone marrow (BM) where the dormant BCCs survive as cancer stem cells (CSCs). The BM niche maintains BCCs in dormancy, and also mediates dedifferentiation of BCCs to CSCs. Since dormancy can occur at any time during the disease, including decades before clinical diagnosis, it is important to understand how these cells survive to allow for the development of safe treatments. Dormant BCCs establish gap junctional intercellular communication (GJIC) with BM niche such as fibroblasts and mesenchymal stem cells (MSCs). GJIC requires connexin 43 (Cx43) but cannot be a safe target since this connexin is also important for hematopoietic function. This study focused on N-cadherin (CDH2) because it facilitates Cx43-mediated GJIC between BCCs and BM niche cells. We found Cx43 and CDH2 mutually regulated their gene expression. Cloning of the 5′ regulatory regions of CDH2 unraveled DNA sequences as possible elements of repressor and activator transcription. We identified potential transcription factors (TFs) that could regulate CDH2 and showed how miRNAs that could cross GJIC might be responsible for regulating the TFs. The axis developed by CDH2 and miRNAs provide insights into how CDH2 is maintained at low level to sustain BC dormancy. The findings, together with previous findings, provide avenues for therapeutic intervention to safely reverse and target dormant BCCs in the BM niche.