Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

Abstract

Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk.

Keywords: HOXB13; prostate cancer risk.

Figure 1

The genomic architecture of HOX genes and schematic of gene expression in embryonic development. Notes: (A) Humans have four clusters of HOX genes on different chromosomes, labeled Cluster A through Cluster D. Each cluster comprises a variable subset of the 13 homology-based HOX gene subtypes. The relative order of the subtypes is preserved across clusters. This conserved ordering is attributed to the genomic duplication-based mechanism by which the clusters arose. (B) During embryonic development, HOX genes are expressed sequentially in partially overlapping zones along the anterior-posterior axis, a phenomenon called collinearity. Accordingly, HOX13 paralogs, including HOXB13, are expressed in posterior regions of the embryo and direct development of the spinal cord, digestive tract, and urogenital system. Abbreviation: HOX, homeobox gene.