There is a large population of breast cancer high-risk women who are also on antipsychotics in the U.S. Antiestrogen treatment is the only FDA-approved therapy for preventing breast cancer, but it requires prolonged and continuous treatment. Consequently, women who are still cancer-free often decline antiestrogen prevention or discontinue the treatment prematurely. The overall goal of this proposal is to test a novel concept in breast cancer prevention for women on antipsychotic dopamine antagonists. Our preliminary data suggest the following hypothesis: Dopamine-antagonizing neuroleptics activate STAT5 and STAT3 in preexistent early precancerous lesions in the breast. These two STAT proteins suppress the apoptosis anticancer barrier in these early lesions and accelerate their progression to cancer. Consequently, intermittent treatment to block STAT5 and STAT3 activity can effectively prevent breast cancer in high- risk women on dopamine-antagonizing neuroleptics. Three aims are as follows: Specific Aim 1. To determine whether in rodent models bearing mammary early lesions, dopamine-antagonizing neuroleptics activate STAT5 and STAT3 in these early lesions, suppress apoptosis, and accelerate progression to cancer. Specific Aim 2. To determine whether in early lesion-bearing rodents on dopamine-antagonizing neuroleptics, genetic ablation of STAT5 and/or STAT3 restores apoptosis in these early lesions and slows the progression to cancer, and to discover the molecular mechanism by which neuroleptic treatment activates STAT3. Specific Aim 3. To determine whether in early lesion-bearing rodents on dopamine-antagonizing neuroleptics, short- term or intermittent treatment to block STAT5/3 activity prevents mammary tumors.