Breast cancer (BC) remains a clinical problem. This is partly due to the existence of dormant BC cells (BCCs) in the bone marrow (BM) that could resurge decades after cancer remission. Cancer stem cells (CSCs) establish themselves in cycling quiescence within the BM microenvironment by forming gap junctional intercellular communication (GJIC) with mesenchymal stem cells (MSCs) and the hematopoietic supporting stroma. MiRNAs can be exchanged between the CSCs and other BM cells through the gap junction to impart cycling quiescence of the CSCs. Although the CSCs express several members of the connexin (Cx) family of proteins, GJIC between CSCs and BM cells requires Cx43. Preventing the formation of GJIC between CSCs and endogenous BM cells enhanced cycle of the BCCs with enhanced chemosensitivity. Since Cx43 is also involved in hematopoietic regulation, in order to identify targets to reverse dormancy, this study investigated the molecular mechanisms by which Cx43 is regulated, including the role of N-cadherin as a facilitator of GJIC between CSCs and BM cells. CSCs are epithelial-mesenchymal cells (EMT) and therefore express N-cadherin. In other studies Cx43 has been shown to interact with N-cadherin to facilitate the movement of Cx43 to the cell membrane. To this end, we hypothesize that the intracellular complex formed by N-cadherin and Cx43 in CSCs is regulated by the chemokine CXCL-12. MDA-MB-231, MDA-MB-468 and T47D were stimulated with different levels of CXCL12. At different times, the expression of N-cadherin was studied by real time PCR, confocal microscopy and flow cytometry. The results showed CXCL12 regulated both N-cadherin and Cx43. However, the outcome on their expression depended on the invasiveness of the tumor. Direct interaction between N-cadherin and Cx43 was demonstrated by time-line tracking for co-localization, molecular modeling and immunoprecipitation. In summary, this study showed that co-localization of N-cadherin and Cx43 is controlled by low level of CXC12. Ongoing studies are investigating how these findings affect GJIC between CSCs and BM stroma/MSCs.

Citation Format: Garima Sinha. Role of N-cadherin in connexin 43 mediated gap junctional formation between dormant breast cancer cells and bone marrow mesenchymal and stromal cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2537.