Homeobox genes: Potential candidates for the transcriptional control of the transformed and invasive phenotype

Abstract

The transformation of a cell and the acquisition of the invasive and metastatic phenotype result from the activation of a group of complex cellular processes rather than from the effect of a single gene product. It is likely that the coordination of the multiple genes involved in malignancy is under the control of a few genes that act as master genes or orchestrator genes. The latter probably code for transcription factors that control the genetic program for tumor invasion and metastasis. Homeobox genes are a family of transcription factors that contain a 183 bp highly conserved nucleotide sequence coding for a 61 amino acid domain that binds specifically to DNA. First discovered in Drosphila as genes controlling segmentation and segment identity, homeobox genes have since been identified in many other species including nematodes, frog, mouse and human. There is strong support for the suggestion that homeobox genes play a key role in development and differentiation. In humans, there are 38 homeobox genes organized in four clusters that are localized on chromosomes 2, 7, 12 and 17. The specific functions of each of these genes are generally unknown. Alterations in expression of several homeobox genes have been reported in a variety of malignant lesions, suggesting that they could play a role in the development of cancer. Using reverse transcriptase reaction coupled with polymerase chain reaction and degenerate oligonucleotides corresponding to the 5′ and 3′ ends of the highly conserved homeodomain, we amplified 130 bp cDNA fragments from the human breast cancer cell line MCF7 that were subsequently cloned into pBluescript vector. Sequencing of the clones, resulted in the identification of the homeodomains of four different human homeobox genes: HOXB6, HOXA1, HOXA10 and HOXC6. Further studies should determine the specific role of these four homeobox genes in the development and progression of human breast cancer and potentially determine if they might be good targets for gene therapy.