According to current estimates of the American Cancer Society, more than 215,990 new cases of invasive breast cancer will be diagnosed and 40,110 American women will die of this disease this year (American Cancer Society 2004 Breast Cancer Facts and Figures 2003-2004, Atlanta, GA). Unfortunately, studies of loco-regional treatment of breast cancer established that many patients with localized disease suffer from micro metastasis. Such microscopic tumors often are not eliminated by surgery, radiation, and chemotherapy and grow to relevant size causing multi-organ dysfunction and eventual death. Therefore, in addition to currently available treatment modalities, effective novel therapies that prevent or eradicate breast cancer dissemination or recurrence are needed. Chemotherapy is one of the most frequently applied treatments of breast cancer. It can be most effective provided there is optimal intratumoral drug uptake to kill most tumor cells as well as lack of chemoresistance, thus assuring that prolonged and repeated application of chemotherapeutic drugs is optimally effective. Recently, it has become increasingly evident that growth and progression of breast tumor cells not only depends on their malignant potential, but also on a variety of growth factors and cells present in the surrounding environment called the tumor stroma. Fibroblasts are a prominent component of this stroma, encompassing up to 80% of the breast tumor mass, and produce substances, which interfere with drug uptake by tumors and thus increase resistance against chemotherapy. Consequently, the treatment strategy in our proposed studies will focus on targeting fibroblast activation protein (FAP), an enzyme specifically overexpressed on more than 90% of fibroblasts in the breast tumor stroma. This will be accomplished by utilizing a DNA vaccine encoding FAP, which is specifically delivered to secondary lymphoid tissue by non-infectious, mutated Salmonella typhimurium. This vaccine strategy induces a strong cytotoxic T cell response specifically killing fibroblasts in the tumor stroma. Eradication of these fibroblasts increases uptake of chemotherapeutic drugs at the tumor site and renders tumor cells more sensitive to chemotherapy. Therefore, the combination of the FAP vaccine along with chemotherapy has the potential to significantly improve treatment outcome of chemotherapy and appears to be a promising means to eradicate established disseminated breast cancer metastases and prevent recurrence of this disease. Based on preliminary results obtained with just such a combination, we will attempt to optimize this strategy and apply it in a mouse model system of spontaneous metastatic breast cancer. It is anticipated that, once proven successful in such animal model systems, this combination therapy could eventually be tested in clinical applications.