Cas Signaling in Breast Cancer
Abstract
Antiestrogens have proven to be effective in the treatment of hormone-responsive breast cancer. In metastatic breast cancer, antiestrogens lead to a response in nearly one half of patients. Resistance to antiestrogens, however, is a serious clinical problem. About 40% of ER-positive tumors fail to respond to antiestrogen therapy, and most breast tumor patients that initially respond will eventually develop resistance. A recent mutagenesis approach has identified three independent loci associated with antiestrogen resistance, and the target genes of two of the loci, BCAR1 and BCAR3, have been characterized. Sequence analysis of BCAR1 demonstrated it to code for the docking protein p130Cas (Cas), which we and others have previously identified to be a key molecule in intracellular signaling pathways. Subsequent studies demonstrated that enhanced activation of Cas signaling can induce antiestrogen resistance, at least in cell culture conditions. Recent studies have demonstrated that Cas is likely to have a relevant role also in clinical breast cancer; studies on breast cancer samples have shown that high levels of Cas expression correlate with poor relapse-free and overall survival, and the response to tamoxifen therapy in patients with recurrent disease was found to be reduced in patients with primary tumors that expressed high levels of Cas. Our hypothesis supported by our preliminary data was that Cas has an important causal role in the development of antiestrogen resistance. As a corollary, understanding of the pathways that Cas activates may identify key regulators of antiestrogen resistance and novel clinical targets for breast cancer treatment, and measurements of Cas signaling levels may provide useful prognostic information for breast cancer patients. In this grant, our objective was to test our hypothesis, and to identify and characterize the signaling pathways that mediate Cas-induced antiestrogen resistance.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2007
- Accession Number
- ADA474700
Entities
People
- Kristiina Vuori
Organizations
- Sanford Burnham Prebys Medical Discovery Institute