Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTWe hypothesize that immune responses to HER3 will block HER3 mediated endocrine-resistance, provide an effective therapy for endocrine-resistant patients, and eliminate the emergence of resistant clones. The study objective is to generate a clinically applicable HER3 cancer vaccine using advances in vector design that will optimize vaccine performance in clinical settings. Our preliminary data suggests that a vaccine targeting HER3 can generate polyclonal HER3 specific immune responses that have antitumor activity. Our translational studies intend to generate a GMP version of our HER3 vaccine, test its safety and immunogenicity, and then first evaluate whether HER3 vaccination in combination with standard anti-hormonal therapy in an anti-hormonal resistant population leads to increased efficacy of the standard therapy. These studies will support the long term goal of vaccinating against HER3 to prevent resistance. We have generated 4 different Ad5(E2b-)HER3 vectors and confirmed induction of anti-HER3 cellular and humoralimmune response and antitumor effect by Ad-HER3 vaccine in mice as preclinical basis for selection of vector construct for clinical use. We have established multiple Tamresistant ER+/HER3 expressing human breast cancer cell lines and developed HETR3 activated pathway signatures using heregulin (HRG) as an activator of the HER3 pathway. These models will be used to identify the protein architecture associated with HER3 pathway activation. SUBJECT TERMS