The long term goal of this study is to prevent breast cancer progression by vaccination. New or over-expressed antigenic peptides presented by class I MMC are candidate tumor antigens. Peptide vaccination will be successful in preventing tumorigenesis if a panel of immunogenic peptides with overlapping expression by the majority of breast cancer cells are administered in a form which induces potent in vivo CTL response. The efficacy of tumor peptide vaccines will be tested in a mouse mammary tumor progression system with defined preneoplastic lesions. A fusion protein will be generated which contains H-2 Kd covalently linked to mouse mammary tumor virus (MMTV) peptide E474 expressed by tumor cells arising from BALB/c D2 preneoplastic hyperplastic alveolar nodule. The peptide in this fusion protein is not released from the complex and does not have to compete with natural peptides for MHC presentation. This stable and homogeneous presentation of tumor antigens in the peptide/MHC complex is expected to induce CTL with greatly enhanced frequency.
Specific Aim l is to test the induction of anti-tumor cytolytic T lymphocytes by fusion proteins which contain immunogenic peptides covalently linked to H2Kd. Immunization of healthy individuals carrying preneoplastic lesions is not without risk. The form and route of vaccination, the efficacy of tumor inhibition, the potential of inducing or selecting for nonimmunogenic tumor variants and the possible induction of autoimmunity must be evaluated in the truly syngeneic preneoplasia --> tumor progression system.
Specific Aim 2 is to test the effect of MMTV peptide vaccination on mammary tumor progression. The tremendous potential of tumor peptide vaccination is in contrast to the paucity of known human breast cancer associated antigens. Therefore, novel antigenic molecules will be identified from overexpressed mRNA by differential display using preneoplastic and neoplastic cells derived from the human breast epithelial cell line MCF-l0.
Specific aim 3 is to identify novel breast cancer associated antigens in preneoplastic and neoplastic cells derived from a human breast epithelial cell line MCF-l0. With the establishment of a breast cancer peptide panel, human breast cancer vaccines can be generated following the format established with mouse mammary tumor vaccines.
