c-Myc, a proto-oncogene that is implicated in tumorigenesis, embryonic development and apoptosis, can physically associate with BRCA1. We have found that BRCA1 interacts with c-Myc in yeast, in in vitro assays and in mammalian cells. Endogenous interactions between BRCA1 and c-Myc were also observed. Efficient BRCA1-Myc association requires the intact helix-loop-helix region of c-Myc, a motif involved in Myc-Max dimerization. BRCA1 does not however bind to Max. Our studies revealed that BRCA1 represses Myc-mediated transcription while having no effect on some other transcriptional activities. Furthermore, BRCA1 reverses the phenotype of embryonic fibroblasts transformed by the activation of Myc and Ras, but only minimally affects the transformed phenotype induced by SV40 virus. These data indicate that BRCA1 may function as a tumor suppressor by regulating the behavior of c-Myc and provide a molecular explanation for some of the effects of the BRCA1 gene product.