Overcoming Tamoxifen-resistance in Breast Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Kristiina  Vuori , M.D., Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9WB-0055 Award: $281,370
Award Type: STEP Award
Research Priorities
Pathogenesis>Too much cell growth: defective messages and internal signaling



Initial Award Abstract (2003)
Antiestrogens, particularly tamoxifen, have proven to be effective in the treatment of breast cancer. Resistance to tamoxifen, however, is a serious obstacle in the management of breast cancer. About 40% of ER-positive tumors fail to initially respond to tamoxifen therapy, and of those breast tumors initially responding to tamoxifen many will eventually develop resistance. Thus, a better understanding of the mechanism of antiestrogen resistance could guide and promote new therapeutic strategies for breast cancer treatment. Recent studies have demonstrated that an intracellular signaling molecule, named “Cas”, induces resistance to tamoxifen in cell culture conditions. Furthermore, studies on clinical breast cancer samples have shown that the response to tamoxifen therapy is reduced in patients with primary tumors that express high amounts of Cas. Taken together, these findings strongly suggest that Cas has a causal role in the development of tamoxifen resistance. Our goal is to more completely identify the molecular mechanisms by which Cas confers antiestrogen resistance in breast cancer cells.

We will utilize molecular and cell biological means to analyze the significance of known Cas-interacting molecules in antiestrogen resistance. Our working model is that Cas interacts with two other molecules, called Crk and BCAR3, and the Rac-JNK pathway is a common pathway with Cas in tamoxifen resistance. Our approach to study Cas involves using a special screening method to detect Cas phosphorylation sites critical to function, and to use gene array technology to find genes associated with resistance. Finally, we will also use a “proteomics” approach to identify mechanisms by which Cas signaling becomes aberrantly activated in breast cancer cells.

In the present project, we will combine our prior expertise on Cas-mediated signaling in normal cells with powerful novel technologies to examine the molecular mechanisms underlying antiestrogen resistance in breast cancer cells. We anticipate that a successful completion of our studies will form an important basis for the development of prognostic tools for antiestrogen therapy, as well as yield new information that will facilitate pharmacological intervention of antiestrogen resistance.


Final Report (2005)
Antiestrogens, particularly tamoxifen, have proven to be effective in the treatment of breast cancer. Resistance to tamoxifen, however, is a serious obstacle in the management of breast cancer. About 40% of estrogen receptor (ER)-positive tumors fail to respond to tamoxifen therapy, and most breast tumors that initially respond to tamoxifen will eventually develop resistance to the treatment.

Recent studies have demonstrated that an intracellular signaling molecule named Cas induces resistance to tamoxifen in cell culture conditions. Furthermore, studies on clinical breast cancer samples have shown that the response to tamoxifen therapy is reduced in patients with primary tumors that express high levels of Cas. Taken together, these findings suggest that Cas has a causal role in the development of tamoxifen resistance. Our goal with this project was to confirm this causal role, and to identify the molecular mechanisms by which Cas confers antiestrogen resistance in breast cancer cells.

To achieve this goal, we have expressed Cas and the two downstream signaling proteins, Crk and BCAR3, in two breast cancer lines. This allows us to study the signaling pathways downstream of Cas that mediate antiestrogen resistance and regulate cell growth. Results of these studies, which are in the manuscript submission and preparation stages, show that BCAR3 (also known as SHEP) is a more likely mediator of Cas-associated antiestrogen resistance. We have ruled out the Crk pathway in these studies.

Our future focus will be to understand in detail the role of the BCAR3 protein and other factors in antiestrogen resistance. Thus, this project has allowed us to test our underlying hypothesis of the complex signaling network that may underlie antiestrogen resistance, and define our focus on putative key signaling pathways. Second, we have generated a unique set of very rigorous reagents (i.e. cells lines and expression vectors) in this important scientific field. We anticipate that a successful completion of our studies will form an important basis for the development of pharmacological intervention of antiestrogen resistance in the future.