INTRODUCTION AND OBJECTIVES: HOXB13 expression is involved in normal prostate development, is a known regulator of androgen receptor (AR)-mediated transcriptomes in prostatic tissue, and is also maintained in the formation of prostatic adenocarcinoma (PCa). In breast and other hormone-sensitive gynecological cancers, deregulated expression of HOXB13 correlates with aggressive tumor phenotypes and poor response to hormonal therapies. The predictive role of HOXB13 expression within prostate tumor progression and its associated outcomes remains unexplored. METHODS: We utilized HOXB13 RNA transcriptome expression from several datasets of PCa radical prostatectomy (RP) genome-wide expression profiles from the Decipher GRID registry and public cohorts (n=6,679). We compared levels of HOXB13 expression by tumor progression and by histology (adenocarcinoma, neuroendocrine/small cell). We assessed the association of HOXB13 expression with pathologic/oncologic outcomes and risk of metastasis based on genomic signatures (Decipher score). Finally, we analyzed gene expression profiling of canonical AR and AR-V7 targets to investigate the association of HOXB13 with AR signaling. RESULTS: There was a stepwise increase in the expression of HOXB13 from benign tissue, to primary tumor, to metastatic PCa (p=0.01). Increased levels of HOXB13 expression were associated with higher pathologic grade group (p<0.001), metastasis (p=0.001), and higher Decipher scores (p<0.001). In two retrospective cohorts (Hopkins, Mayo), higher HOXB13 expression was associated with decreased metastasis-free survival (p=0.02 and p=0.003, respectively). HOXB13 expression was also highly correlated to AR/AR-V7 target genes, NKX3-1 (r=0.73), and FOXA1 (r=0.67). Lower HOXB13 was associated with neuroendocrine biomarkers NCAM1 and ASXL3. Furthermore, HOXB13 expression was decreased in metastatic castrate-resistant PCa and neuroendocrine and small cell prostatic carcinoma (p<0.001). CONCLUSIONS: In primary PCa, HOXB13 expression increases with progression and is associated with higher AR signaling and adverse pathologic and oncologic outcomes. Though, its expression is lowered when PCa becomes castrate-resistant and when these cancers develop neuroendocrine differentiation. These data support the hypothesis that increased levels of HOXB13 confer a more aggressive PCa phenotype with metastatic potential. Future research can explore the role of HOXB13 not only as a biomarker of aggressive disease but also as a therapeutic target in PCa.None.
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