Increased levels of the
calcium-binding protein neuronal calcium sensor 1 (NCS1) predict an unfavorable patient outcome in several aggressive
cancers, including breast and liver
tumors. Previous studies suggest that NCS1 overexpression facilitates metastatic spread of these
cancers. To investigate this hypothesis, we explored the effects of NCS1 overexpression on cell proliferation, survival, and migration patterns in vitro in 2- and 3-dimensional (2/3-D). Furthermore, we translated our results into an in vivo mouse xenograft model. Cell-based proliferation assays were used to demonstrate the effects of overexpression of NCS1 on growth rates. In vitro colony formation and wound healing experiments were performed and 3-D migration dynamics were studied using
collagen gels. Nude mice were injected with
breast cancer cells to monitor NCS1-dependent
metastasis formation over time. We observed that increased NCS1 levels do not change cellular growth rates, but do significantly increase 2- and 3-D migration dynamics in vitro. Likewise, NCS1-overexpressing cells have an increased capacity to form distant
metastases and demonstrate better survival and less
necrosis in vivo. We found that NCS1 preferentially localizes to the leading edge of cells and overexpression increases the motility of
cancer cells. Furthermore, this phenotype is correlated with an increased number of
metastases in a xenograft model. These results lay the foundation for exploring the relevance of an NCS1-mediated pathway as a metastatic
biomarker and as a target for pharmacologic interventions.-Apasu, J. E., Schuette, D., LaRanger, R., Steinle, J. A., Nguyen, L. D., Grosshans, H. K., Zhang, M., Cai, W. L., Yan, Q., Robert, M. E., Mak, M., Ehrlich, B. E.
Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of
breast cancer cells in vitro and in vivo.