Mechanisms of Intercellular Communication During Breast Cancer Progression Through Metastasis

Breast cancer is the second leading cause of cancer-related death in women worldwide. Despite more frequent and efficient screening measures, subtype-specific treatments, and overall improved patient outcomes, metastasis remains difficult to treat and accounts for 90% of breast cancer patient deaths. While the role of intercellular communication in metastasis, either among cancer cells, or between cancer cells and the tumor microenvironment is well established, additional research on specific molecular and cellular mechanisms underlying these interactions is necessary to develop novel therapeutic strategies. One mechanism that facilitates metastasis is epithelial-mesenchymal transition (EMT), which can be induced in cancer cells following the secretion of growth factors by tumor-associated macrophages (TAMs). During EMT, epithelial cells lose their cell-cell junctions, resulting in an alteration of intercellular communication. One of the junctions lost during EMT is gap junctions composed of connexin43 (Cx43), however, this is paired with an increase in expression of cytoplasmic Cx43 which binds microtubules. To elucidate the role of cytoplasmic Cx43 during EMT and breast cancer metastasis, we utilize a Cx43 mutant that has reduced binding with microtubules. We demonstrate disruption of the interaction between Cx43 and microtubules decreases mesenchymal marker expression and cell migration in vitro during EMT, and reduces breast cancer metastasis to the lungs in vivo, identifying a novel non-junctional tumorigenic role for Cx43 in metastasis and a potential therapeutic target in the treatment of breast cancer.