Immunity to murine breast cancer cells modified to express MUC-1, a human breast cancer antigen, in transgenic mice tolerant to human MUC-1

The high incidence of breast cancer in women and the severity of the diseas e have stimulated a need for improved and novel forms of therapy. The produ ct of the MUG-I gene has been identified as a breast cancer-associated anti gen in breast cancer patients. The gene has been cloned and sequenced. Tran sgenic mice were prepared that express human mucin and are naturally tolera nt to the molecule, providing a unique opportunity to investigate immunothe rapeutic strategies in experimental animals that might eventually be applie d to breast cancer patients. A cell line (410.4) derived from a mouse mamma ry adenocarcinoma that arose in a BALB/c mouse was transduced with a retrov iral vector (R1-MUC1-pEMSVscribe) that encoded MUG-1. After confirmation of the expression of human mucin, the cells (E3) were further modified by tra nsduction with retroviral vectors encoding interleukin (IL)-2, IL-4, IL-12, or IFN-gamma to evaluate the effect of cytokine-secretion on the immunogen ic properties of the cells in the MUC-1 transgenic mice. The results indica ted that modification of the breast canter tells to secrete IL-12 reduced a nd at times eliminated the tumorigenic growth properties of the cells. Unde r similar circumstances, progressively growing tumors formed in MUC-1 trans genic mice that received injections of unmodified E3 cells or with E3 cells modified to secrete IL-2, IL-4, or IFN-gamma, Immunity to breast cancer de veloped in MUC-1 transgenic mice that had rejected IL-12-secreting E3 cells because the animals were resistant to challenge with (non-cytokine-secreti ng) E3 cells. In vitro analyses confirmed the presence of T cell-mediated c ytotoxicity toward the breast cancer cells in MUG-I transgenic mice immuniz ed with the IL-12-secreting cells. Our data obtained in a unique animal mod el system point toward an analogous form of therapy for breast cancer patie nts.