The products of a growing number of genes have been shown to display seemingly contradictory functions; namely, the induction of tumorigenesis and the induction of apoptosis. Heregulin's involvement in oncogenesis occurs through its interactions with members of the EGF receptor tyrosine kinase family. Recently one isoform of heregulin, beta2b, was isolated in an in vitro screen for dominant, apoptosis-inducing genes in kidney epithelial cells. Here we show that heregulin is also capable of mediating apoptosis in human and murine mammary tumor cell lines and murine tumors. Furthermore, through transfection of the human breast cancer cell line MCF-7 with the truncated transmembrane/cytoplasmic segment of the heregulin gene, we show that the intracellular region of the heregulin precursor is sufficient for induction of apoptosis. Through the use of DNA fragmentation assays we also show that apoptosis occurs in cell lines established from heregulin-induced mammary gland tumors. TdT addition of digoxigenin labeled nucleotides to 3' OH ends of DNA breaks recapitulated these results in the actual tumors. Finally, over-expression of heregulin is shown to lead to the down-regulation of Bcl-2, an inhibitor of apoptosis. Conversely, the transfection of Bcl-2 into MCF-7 cells inhibits heregulin-mediated programmed cell death.