Homeobox genes control developmental patterning and are increasingly being found to be deregulated in tumors. The DLX4 homeobox gene maps to the 17q21.3-q22 region that is amplified in some epithelial ovarian cancers. Because amplification of this region correlates with poor prognosis, we investigated whether DLX4 overexpression contributes to aggressive behavior of this disease. DLX4 was not detected in normal ovary and cystadenomas, whereas its expression in ovarian carcinomas was strongly associated with high tumor grade and advanced disease stage. Overexpression of DLX4 in ovarian cancer cells promoted growth in low serum and colony formation. Homeobox genes constitute an evolutionarily conserved superfamily of genes that play essential roles in controlling cell differentiation and morphogenesis during embryonic development.1 Members of this gene superfamily encode transcription factors and have been increasingly reported to be up-or down-regulated in a variety of cancers.2,3 Although the functional significance of many of these genes to tumor progression has yet to be defined, recent studies indicate that their aberrant expression promotes self-renewal, cell proliferation, and survival.2,3 For example, HOXA5 regulates the p53 promoter and its expression is lost in Ͼ60% of breast cancers. 4 On the other hand, overexpression of SIX1 in breast cancers induces cyclin A1 and deregulates cell cycle control.
5Various mechanisms give rise to aberrant homeobox gene expression in tumors. NKX3.1 maps to a region that frequently undergoes loss of heterozygosity in prostate intraepithelial neoplasia and prostate cancers, and NKX3.1 loss is thought to be an important initiating event in prostate neoplasia. 6,7 Loss of expression of HOXA5 in breast cancers and of HOXA10 in endometrial cancers has been attributed to promoter methylation. 4,8 Deregulation of many homeobox genes in leukemias is attributable to chromosomal translocations.3 Very few reports attribute overexpression of homeobox genes in solid tumors to gene amplification. One notable example is amplifications within the 17q21-q22 region that occur in ϳ10% of breast and ovarian cancers and are associated with poor prognosis. 9 -11 This region contains the HOXB gene cluster. HOXB7 and HOXB13 are members of this cluster and are overexpressed in breast and ovarian cancers.12-15 HOXB13 has been reported to promote invasiveness of breast and ovarian epithelial cells.