There is growing evidence to suggest that changes in expression of the adapter protein p130cas (Cas) in breast tumors may contribute to cancer progression and poor prognosis. In human breast tumors, Cas overexpression is correlated with a high probability of recurrence and a high incidence of intrinsic resistance to the antiestrogen tamoxifen. Antiestrogen resistance is also evident in cultured breast cancer cells that overexpress either Cas or its binding partner AND-34/BCAR3. Cas is comprised of multiple structural domains, each of which has the capacity to interact with a different array of proteins and thus promote potentially distinct functional outcomes. We hypothesize that overexpression of Cas or AND-34 activates signaling pathways through interactions with a defined subset of these proteins, ultimately leading to antiestrogen resistance and changes in cell physiology that are associated with aggressive tumor behavior and poor prognosis. This hypothesis will be tested in Aim 1 by identifying domains and downstream effectors of Cas and AND-34 that function to promote antiestrogen resistance, and investigating how these pathways coordinate with or override estrogen receptor functions during this process.
In Aim 2, we will test whether Cas overexpression in cells that serve as models for early-stage breast cancer can induce changes in cell physiology and morphology that coincide with the acquisition of a more aggressive growth and invasion phenotype. Conversely, we will also test whether inhibition of Cas expression or function in cells that serve as models for late-stage breast cancer reverses some of the deleterious phenotypes exhibited by these cells. The potential functional contribution of proteins known to bind to domains that are implicated in the studies described above will be pursued in the context of each of the two Specific Aims. However, in those instances where a domain is implicated that does not have a known binding partner, or when none of the known binding proteins are found to play a role, attempts will be made in Aim 3 to identify additional binding partners and test whether they function in these pathways. Completion of this work will open new avenues of investigation into such areas as the development of molecular screens for predicting responses to tamoxifen treatment, the design of strategies for enhancing the efficacy of tamoxifen in intrinsically resistant patients, and the application of novel molecular approaches to slow tumor progression.
