| In all cancers, including those of the breast, there is a disruption of the delicate balance between cell proliferation and apoptosis, leading to abnormal cell growth. Increased cell motility is also a common feature of breast cancer, as subsets of cells that are able to traverse the basal lamina and enter surrounding tissues have the potential to form metastases at distant sites. Cell growth and migration are both controlled by a complex network of signal transduction pathways, and this complexity is reflected in the genetic heterogeneity of sporadic breast cancer. However, mammary epithelial cells and many early breast tumors are dependent upon the nuclear hormone estrogen for proliferation. Inhibition of estrogen-dependent growth has the potential to be a highly successful therapeutic strategy in the treatment of breast cancer, but resistance to antiestrogens, including tamoxifen, is a significant clinical problem.; This thesis examines the involvement of c-Src, Cas, and AND-34 in cell growth, cell migration, and antiestrogen resistance in breast cancer cells. The association of c-Src with the adapter protein Cas leads to increased Src kinase activity, and this correlates with the induction of cell motility. These data may help to reconcile how high endogenous levels of both Cas and c-Src could contribute to the elevated Src kinase activity observed in many breast tumor cells. Expression of the guanine nucleotide exchange factor AND-34, a Cas binding partner, significantly enhances Cas-mediated Src activation and cell migration, suggesting that this molecule may also participate in abnormal cell growth and migration in breast cancer. Furthermore, both Cas and AND-34 can induce estrogen-independence and resistance to tamoxifen in MCF7 breast cancer cells. Through association with the p85 subunit of phosphatidylinositol 3′-kinase, Cas is involved in cellular transformation by the v-crk oncogene, and this has the potential to be important for the activation of PI3K-mediated cell survival pathways in breast cancer cells. Together, these data suggest that modulation of Src activity by Cas and AND-34 may be a critical event in the development of tamoxifen resistance and acquisition of the abnormal cell proliferative and migratory properties observed in breast cancer. |
