Project Summary/Abstract New targeted therapies for breast cancer are needed for patients who do not have indication for targeted therapy (e.g:trastuzumab) in HER2 and/or ER negative tumors. The candidate has a strong background in basic and translational research in cancer biology and molecular therapeutics. She has shown that PEA-15, a novel phosphoprotein, has tumor suppressor properties; binds to ERK, blocking ERK activation. Her long-term goal is to be a independent translational researcher and to use targeted therapies to improve treatment options for patients with breast cancer. To become independent, she requires additional training in 5 areas: (1) training in Investigational New Drug (IND) and Patent applications to translate laboratory research into hypothesis-driven clinical trials; (2) identification of mouse models with most efficient knockdown using siRNA (3) metastasis assays, epithelial-to-mesenchymal transition (EMT) and angiogenesis; and (4) training in leadership skills. She has identified highly experienced co-mentors who are committed to helping her develop her skills in these areas. One is an expert in developing novel targeted therapies and the other has developed a novel liposomal in vivo siRNA delivery system. The primary objective is to define the role of ERK in HER2-negative breast cancer, and to develop ERK as a therapeutic target. The central hypothesis is that suppressing ERK reduces tumorigenicity and metastasis in breast cancer. The 3 specific aims are: (1) Determine whether suppressing ERK inhibits tumorigenicity in HER2-negative breast cancer cells. (2) Determine the impact of ERK inhibition on EMT in HER2-negative breast cancer cells (3) Determine the role of the ERK modulator PEA-15 in HER2-negative breast cancer. Three different approaches will be used to suppress ERK: siRNA to knock down ERK, PEA-15 gene therapy to sequester ERK, and treatment with an inhibitor of MEK, which lies upstream of ERK. At the conclusion, she will determine if ERK pathway would be a useful molecular target for treatment of such disease. The candidate will use her extensive training to pursue independent research on ERK modulator resistance in tumorigenicity/metastasis, and development preclinical data which will lead to ERK targeted clinical trials in breast cancer.