Germline HOXB13 G84E Mutation Inhibits MEIS1-HOXB13 Driven Tumor Suppression in Prostate Cancer

Prostate cancer (PrCa) continues to pose a burden to adult men in the United States, having the highest incidence and second highest mortality rates. A prostate cancer diagnosis in an immediate family member increases risk 2-3 fold. Standard of care treatment of PrCa targets the Androgen Receptor (AR) which accounts for mostly somatic mutations and are less likely to work if a PrCa progresses to Castration Resistant Prostate Cancer (CRPC), emphasizing the need in identifying and understanding other signaling axis. Germline mutations in the developmental transcription factor HOXB13 are nonspecifically associated with early onset and potentially rapid progression of prostate cancer, with no confirmation. The G84E mutation on HOXB13 was studied in the context of HOXB13’s tumor suppressive co-transcription factor, MEIS1, yielding dysregulation of proteoglycans consistent with a loss-of-function HOXB13 status. The G84E mutation resulted in faster onset and progression of 22Rv1 tumor xenografts in SCID mice and were confirmed to have a significant reduction in the proteoglycans, Decorin and Lumican. Exogenous addition of Decorin and Lumican reduced growth and migration of PrCa cell lines. These data support the HOXB13-MEIS1 axis in PrCa while providing a foundation for emerging proteoglycan therapies in the CRPC space when AR targeting therapies are no longer effective.