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.

HOXB13 and ALX4 induce SLUG expression for the promotion of EMT and cell invasion in ovarian cancer cells

“…The most commonly observed mutation is the substitution of glycine at amino acid residue 84 to glutamic acid (G84E), but the mechanism by which the mutation confers risk has not yet been determined [ 34 , 35 ]. HOXB13 promotes or represses prostate cancer cell proliferation depending on the cellular context, such as with androgen receptor expression [ 36 ]. HOXB13 has opposing functions in other cancers as well.…”

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

“…Unlike for FOXA1, no somatic mutations in HOXB13 have been detected in primary prostate cancer or in the metastatic disease. However, a recurrent germline mutation HOXB13 (G84E) has been identified (Ewing et al 2012), which is associated with increased prostate cancer risk (Decker & Ostrander 2014). Recently, more hereditary HOXB13 mutations conferring increased risk of prostate cancer have been reported (Maia et al 2015).…”

Homeobox B13 G84E Mutation and Prostate Cancer Risk

“…The homeobox B13 ( HOXB13 ) gene is involved in prostate development [1], and in vitro results have suggested that its transcription factor is involved in prostate cancer (PCa) cell growth through androgen receptor interaction, regulation by FOXA1 , and other pathways [2]. The HOXB13 missense mutation G84E is a founder mutation in Nordic populations [3], with reported carrier frequencies of 0.2–1.4% [4], [5], [6], [7], and is carried by 0.1–0.5% in other Western European populations [4], [8].…”