Abstract 346: Functional role for axonal guidance molecule Sema7A in breast cancer metastasis: Epithelial to mesenchymal transition and tumor metastasis

Reactivation of embryogenesis related processes such as neurogenesis is a powerful mechanism used by tumor cells to enhance their survival and propagation. Recent studies have shown that many types of solid tumors express neurogenic molecules independent of the tumor's geography. Semaphorins are a compelling example of these pleiotropic neuronal molecules. Semaphorins were originally characterized for their role in axonal guidance and several of them have been found to play a role in cancer and other inflammatory diseases. Of the Semaphorins, Semaphorin7A (Sema7A) has not yet been studied in the context of cancer. It has however been associated with fibrosis, inflammation and immune modulation. Most semaphorins are repellent cues and inhibit cellular migration, but Sema7A is the only vertebrate semaphorin that serves as an axon chemoattractant. Sema7A also promotes dendricity, adhesion and motility during neuronal development, monocyte differentiation and osteoclast development. All these cellular properties have been attributed to Sema7A's ability to activate p38 mitogen-activated protein kinase pathway (MAP-kinase) through α1β1 integrins. We have recently discovered that Sema7A is over-expressed in the tumor tissue of breast cancer patients compared to the adjacent normal tissue. Within the tumor tissue, the mesenchymal cancer stem cells had the highest expression of Sema7A. We have also found that breast cancer cell lines of a mesenchymal phenotype express high levels of Sema7A and that transforming growth factor beta-1 can induce Sema7A expression in breast epithelial cells. Further, we show that mice bearing Sema7A gene silenced mammary tumors had decreased tumor growth and metastasis with enhanced survival compared to the control tumors. Our studies aim to unravel the functional role of Sema7A in breast cancer progression. We hypothesize that Sema7A expression in tumor cells may lead to increased tumor cell dendricity, migration, and adhesion through the activation of the MAP-kinase pathway and mediating epithelial to mesenchymal transition (EMT). Similar to its role in neurogenesis, in the tumor microenvironment Sema7A could contribute to tumor cell migration and tissue remodeling. Therefore, Sema7A could prove to be a novel therapeutic target to limit tumor growth and metastasis not only for breast cancer but for other solid tumors as well. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the A