The heterogeneous nature of breast cancer and the correlation of myeloid cell infiltration with accelerated tumor progression were recognized early in breast cancer immunology research using murine model systems induced by the mouse mammary tumor virus, chemical carcinogens or hormones. Distinct cell lines established from a single mammary tumor attest to the challenges of controlling tumors with such complexity. Here, we test the feasibility of controlling breast cancer by active vaccination targeting a shared tumor-associated antigen, human ErB-2 (Her-2). Her-2 DNA vaccines were constructed and Her-2 transgenic mice were established. DNA vaccination overcomes Her-2 tolerance to induce anti-tumor immunity which is amplified by the removal of regulatory T cells, but is accompanied by a significant risk of autoimmunity. Her-2 vaccines combined with appropriate immune modulation to trigger in vivo priming to other tumor-associated antigens will be the key to improved breast cancer control.