Loss or mutation of known tumor suppressor genes accounts for a small proportion of all breast cancers. We have recently shown that interferon regulatory factor 1 (IRF1) is a putative tumor suppressor gene in breast cancer. We now report that the A4396G single nucleotide polymorphism in the IRF1 gene is more frequent in human breast cancer cell lines than in the general population (P = 0.01). Furthermore, A4396G is more frequently expressed in African American (black) than in European ancestry (white) subjects (n = 70 subjects; P < or = 0.001), leading to a significant difference in genotype distribution between these populations (P = 0.002).