FDXR Regulates ER-Positive Breast Tumorigenesis via Reprogramming Metabolism

Scientific Objective and Rationale: The majority of breast cancers are estrogen receptor positive (ER+), accounting for most breast cancer-related fatalities. Despite treatment with anti-estrogen therapy, almost 50% of patients with ER+ advanced breast cancer relapse after treatment, highlighting the need for new and more effective therapies. Tumor cells adjust their metabolism to provide essential energy and biosynthesis to fuel uncontrolled growth. This altered metabolism is considered as a hallmark of cancer, an Achilles' heel that is a proven target of successful therapies. One of fundamental questions and challenges for cancer therapy is: What drives breast cancer cell growth and how we can stop it? In order to grow, breast cancer cells need to obtain necessary energy. The most important compartment in the cells for providing the energy is called 'mitochondrion.' Mitochondria are essential for cancer cells to grow. Therefore, if we can inhibit mitochondrial function and stop providing energy in breast cancer cells, we may starve the cancer cells to death. FDXR is a mitochondrial enzyme, we have identified that it promotes mitochondrial function and tumorigenesis in ER+ breast cancer. In this proposal, we examine how it fuels mitochondrial function. More specifically, we found that FDXR controls an important component of mitochondria called Glutathione. Therefore, we hypothesize that FDXR promotes mitochondrial function and tumor growth by regulating Glutathione. Our study aims to study how we can inhibit mitochondrial function in breast cancer. Our objectives are (1) to validate and investigate the mechanism by which FDXR regulates mitochondrial function in ER+ breast cancer and (2) to examine whether targeting FDXR or Glutathione pathway is therapeutically beneficial in a clinically relevant breast cancer system. Career Goals in Breast Cancer: My career goals include: (1) studying key signaling pathway mechanisms in breast cancer; (2) investigating how alterations in gene expression and cell metabolism contribute to breast cancer; (3) elucidating how we can take advantage of these findings to develop therapeutic strategies for breast cancer. I aspire to work at the forefront of both basic and translational research of breast cancer. In the research development plan, the extensive scientific techniques and training will enable me to generate the quality and compelling data, while allowing me to contribute to the understanding of breast tumorigenesis. Continuous exposure to scientific workshops, conferences and seminars will expand my knowledge base and help me remain current on breast cancer research. An excellent mentor committee (Dr. Qing Zhang and Dr. Perou) will supervise and guide my research and ultimately help me with transition to an independent position. Finally, the University of North Carolina SPORE (Specialized Program of Research Excellence) breast cancer program will allow me to collaborate with integrated breast cancer program researchers with clinical, basic, and epidemiological backgrounds. A Breakthrough Fellowship Award will enable me to dedicate my time to the proposed research and allow me to contribute to the understanding of breast tumorigenesis and the development of novel therapeutic interventions that may one day end breast cancer. It will also provide a well-rounded and multidisciplinary experience that will ensure outstanding preparation for independent research by the completion of the 3-year training program. Applicability and Impact: The proposed project has potential applicability for preclinical studies and significant impact on the development of specific and effective therapeutic strategies for breast cancer as indicated by: (1) Our preliminary data showing that FDXR is an essential regulator for tumor metabolism and tumorigenesis in ER+ breast cancer. Understanding how FDXR drives breast cancer cell growth and delineating FDXR-mediated pathway will