Alterations in the control of gene expression is a key event in neoplastic transformation. Investigating the expression of transcription factors such as homeodomain proteins may therefore allow better characterization of molecular mechanisms underlying the transformation process.Expression of homeodomain proteins DLX4 and HB9 was detected by RT-PCR and immunohistochemically in 24 breast tumors and their corresponding non-malignant tissue.Although the percentage of nuclei expressing both DLX4 (p = 0.001) and HB9 (p = 0.0001) is increased in breast carcinoma, their intensity of nuclear staining is decreased compared to non-malignant nuclei. Furthermore HB9 nuclear immunoreactivity decreased progressively with increasing tumor grade (p = 0.001).These data suggest that the reduction in malignant nuclear DLX4 immunoreactivity is an earlier event in breast carcinogenesis than the progressive loss of HB9 expression observed with increasing tumor grade. With further study and in conjunction with standard criterion of pathology, these findings may help to predict the malignant behaviour of some breast cancers.