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. / Doctor of Philosophy / Cancer, which is caused by the uncontrolled growth of abnormal cells, remains one of the top causes for death worldwide. Breast cancer, in particular, is the second leading cause of cancer deaths in women in the United States. With advances in screening and improved/subtype specific treatments, patient outcomes have significantly improved for localized tumors. However, the spread of cancer from the primary tumor to a distal part of the body, called metastasis, remains difficult to treat and accounts for approximately 90% of cancer-related deaths. One mechanism known to facilitate metastasis is a cellular process called epithelial-mesenchymal transition (EMT). During EMT, epithelial cells lose their cell-cell junctions and apical-basal polarity, and gain mesenchymal characteristics, becoming more motile and invasive. These characteristics facilitate the invasion of cancer cells into tissue surrounding the primary tumor as well as entry into the bloodstream and exit at a distal site, subsequently forming a secondary tumor (metastasis). In tumors, EMT is often induced through communication between cancer cells and cancer-promoting immune cells such as tumor-associated macrophages. One of the cell-cell junctions lost during EMT are connexin43 gap junctions, which are channels that facilitate the transfer of small molecules between cells, promoting communication. We utilize mammalian cell lines and a mouse breast cancer model to investigate the role of connexin43 in EMT and breast cancer metastasis. This work provides information that can be used to develop new therapeutics and strategies for the treatment or prevention of breast cancer metastasis.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/118707 |
| Date | 30 April 2024 |
| Creators | Wheeler, Christina Eileen |
| Contributors | Graduate School, Lamouille, Samy Y., Johnstone, Scott Robert, Smyth, James, Cimini, Daniela, Allen, Irving Coy |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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