Defining the Mechanisms of Breast Cancer Dormancy and Metastasis in Vivo
Abstract
Breast cancer is the most common malignancy in women in the United States. Despite tremendous advances in early detection, improved techniques in tumor resection, adjuvant radiation, and early cancer direct therapies, approximately 20%-30% of early-stage breast cancer patients ultimately develop incurable advanced and metastatic disease with high mortality and morbidity. Tumor dormancy, a process in which a few tumor cells that have disseminated to distant organs and escaped conventional therapies suddenly develop into metastatic tumors many years later, is thought to be the major underlying cause for the latency between complete remission after treatment for the primary breast cancer and presentation of metastatic disease. The exact cellular and molecular mechanisms regulating tumor dormancy remain poorly understood due to challenges in detecting single dormant tumor cells in a live organism and characterizing the dynamic dormant environment. Epithelial-mesenchymal transition (EMT) is a complex coordination of a network of transcription factors and signal transduction pathways leading to altered expression of genes in cell adhesion, differentiation, and motility with an important implication for tumor dormancy and chemoresistance. Our lab has established a powerful mouse model in which primary breast tumor cells are labelled with red fluorescent protein and can be traced in circulation and to each dormant sites upon activation of an EMT transcription factor, Twist1. Using this mouse model, the role of EMT in the spatiotemporal regulation and chemoresistance of breast tumor dormancy can be studied. For this Breakthrough Fellowship Award, we propose studies to clearly define the role of EMT in breast cancer dormancy with a combined approach of using a novel breast cancer mouse model developed in our lab and to profile EMT-related gene expression from circulating tumor cells isolated from peripheral blood from metastatic breast cancer patients. Currently, there is no biomarker for chemoresistance or immunotherapy response in metastatic breast cancer. Refinement of circulating tumor cells (CTC) isolation technology has paved the way of liquid biopsies with the potential for expanding into clinical use in risk stratification, disease response monitoring, and early recurrence detection. However, the potential clinical utility of EMT gene signature as a prognostic tool for chemotherapy and immunotherapy response has not been tested. We hypothesize that high expression levels of EMT-related genes on CTC will correlate with poor response to chemotherapy but higher response to immunotherapy in metastatic breast cancer patients. Our Institutional Review Board-approved, prospective, pilot project has recently launched with the goal to investigate a correlation between chemotherapy and immunotherapy treatment response and molecular characterization of CTC from metastatic breast cancer patients. CTC are being isolated using an improved method with a microfluidic device in an unbiased manner, which is superior to the commonly used, positive selection, enrichment system, which isolates only a subset of CTC. Expression profiles of genes involved in EMT and metastasis will then be serially correlated with treatment response. The proposed studies will be conducted by Dr. Kay Yeung under the guidance and mentorship of two experienced breast cancer researchers, Dr. Jing Yang and Dr. Barbara Parker, who each have expertise in basic and clinical research. Dr. Yeung obtained a doctoral degree in studying the molecular regulation of a canonical apoptosis pathway in breast cancer cells and mastered many molecular biochemical and cellular biology techniques. In addition, Dr. Yeung received training in internal medicine and is currently a hematology/oncology fellow at the University of California, San Diego with the goal of becoming an independent physician-scientist focusing on breast cancer. We believe that our proposed studies
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710012
Entities
People
- Kay Yeung
Organizations
- United States Army
- University of California, San Diego