A Novel Preclinical Model of Dormant Metastatic ER+ Breast Cancer
Abstract
Overarching Challenge: Determine why/how breast cancer cells lay dormant for years and then re-emerge (recurrence); determine how to prevent recurrence. Background: Approximately 75% of all breast tumors are estrogen receptor (ER) positive. Although most women with these tumors initially respond well to endocrine therapy, approximately 50% will experience relapse. Moreover, when these tumors recur, they tend be metastatic and therapy-resistant. As a consequence, the majority of breast cancer metastases, as well as the majority of breast cancer fatalities, each year results from ER+ disease. However, unlike ER- breast cancers, which relapse early, ER+ tumors tend to relapse late (from 5 to 20 years post-diagnosis). The high risk for a late recurrence indicates that women with clinically undetectable cancer can have disseminated ER+ tumor cells that survive in a dormant state for years or even decades. Despite this major clinical problem for women with ER+ breast cancer, there are few, if any, preclinical models to study spontaneous dormant-metastatic ER+ disease, so virtually nothing is known about the pathways contributing to an ER+ dormant-metastatic phenotype. Without this knowledge, rational therapeutic strategies cannot be developed to prevent recurrent disease. Objective: We have developed multiple ER+ breast cancer cell lines that exhibit many of the features of a dormant-metastatic breast tumor. Our goal in this proposal is to fully evaluate the behavior of these cell lines in mice to determine if they are a suitable model for dormant-metastatic ER+ disease and to learn about genes that may be involved in the dormancy process. Rationale: Our research has established that activation of a key protein, called IKKbeta, in ER+ breast cancer cells causes the cells to stop proliferating and become highly invasive. When we activated this protein in mammary tumors of mice, the primary tumors regressed and micrometastases could be detected in brain, lung, and lymph nodes, both of which are indicative of dormant-metastatic disease. Moreover, when we turned off the IKKbeta signal, the primary tumors regrew, which is indicative of a local recurrence. In this proposal, we will evaluate the potential of this model and the role of IKKbeta by conducting a series of experiments designed to ask the following questions: (1) How long can these cells survive in the mammary gland and metastatic sites? (2) Can these cells survive endocrine and chemotherapy? (3) Do the micrometastases develop into metastatic tumors when IKKbeta is shut off? (4) What genes are involved in maintaining local and metastatic cell dormancy? (5) Is IKKbeta expressed or active in primary or metastatic tumors of women with ER+ breast cancer? (6) Is IKKbeta activity predictive of a recurrent metastatic tumor in women? Impact: While the results of the cell model cannot immediately be translated to the clinic, a major first step in combatting recurrent/metastatic ER+ breast cancer will have been accomplished. If successful, we believe that the cell lines we developed will fill an urgent need to better model this deadly aspect of ER+ disease. Based on this model, novel therapeutic strategies could be developed to keep dormant cells dormant and prevent recurrence. Alternatively, this model can be used to develop a therapeutic strategy to kill dormant cells. Results of our studies will also provide novel information on whether IKKbeta could be developed as a biomarker of recurrent/metastatic ER+ breast cancer. Together, these endpoints would represent major breakthroughs in new strategies to predict and target dormant metastatic cells and prevent recurrent ER+ breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1610044
Entities
People
- Jonna Frasor
Organizations
- United States Army
- University of Illinois at Chicago