Advanced-stage breast cancer is typically associated with enhanced tumor invasiveness and the development of distant, therapeutically resistant metastases. Metastases are largely considered incurable and result in patients succumbing to the disease. Breast cancer cell migration and invasion are essential for metastasis;therefore, it is critical to understand the molecular mechanisms underlying these processes in order to develop novel treatment strategies and improve overall survival. This fellowship application comprises a training program that includes (1) research, (2) didactic coursework and training, (3) participation in research meetings and seminars, and (4) conferences and community outreach. The research component is focused on understanding the role of a molecule called Breast Cancer Antiestrogen Resistance 3 (BCAR3), which together with the adaptor molecule Breast Cancer Antiestrogen Resistance 1 (also known as p130Cas) and the non- receptor tyrosine kinase c-Src, comprise a signaling network in invasive breast cancer cells. BCAR3 expression increases Cas/c-Src association, c-Src kinase activity, and promotes breast cancer cell migration/invasion. We propose in this study to determine whether BCAR3, a component of the BCAR3/Cas/c- Src signaling axis, enhances breast tumor invasiveness and metastasis by promoting a pro-migratory phenotype in breast cancer cells. We will test the hypothesis that BCAR3 enhances breast tumor invasiveness and metastasis in vivo by using an orthotopic mouse model of breast cancer metastasis (Aim 1A). In parallel, we will determine whether independent and/or co-expression of BCAR3, Cas and c-Src are associated with human breast tumor invasiveness by evaluating their expression levels using breast cancer tissue microarrays (Aim 1B). In order to gain further insight into the role of BCAR3 in promoting breast cancer cell motility, we will use gain-of-function and loss-of-function approaches to study actin cytoskeletal and adhesion remodeling in breast cancer cell lines as a function of BCAR3 expression (Aim 2). Completion of this study will provide new insights into the molecular mechanisms driving breast cancer progression and identify new approaches for treating breast cancer patients. Didactic coursework will provide training in advanced scientific techniques. Participation in research meetings, seminars, and conferences will improve scientific communication skills, and provide exposure to both basic and clinical cancer research. Together, this training plan will provide a solid foundation upon which to build a career as a successful, independent breast cancer researcher.

Public Health Relevance

One of the major challenges in treating breast cancer patients is that the tumor cells can invade, migrate, and metastasize to distant sites within the body. Metastatic disease is largely incurable and typically results in a poor clinical outcome. The proposed research strives to better understand the molecular mechanisms underlying breast cancer cell migration/invasion, tumor progression and metastasis in order to develop more effective therapeutic interventions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-D (20))
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Schmidt, Michael K
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University of Virginia
Schools of Medicine
United States
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