Germline Mutations in HOXB13 and Prostate-Cancer Risk

Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene

HOXB13: INVESTIGATING MECHANISMS OF G84E MUTATION-ASSOCIATED PROSTATE CARCINOGENESIS

Prostate cancer is a commonly diagnosed disease that is highly heritable. To characterize the molecular processes that translate into the array of clinical behavior ranging from indolence to progression and metastasis-driven mortality, the mechanisms underlying the genetic predisposition to prostate cancer need to be investigated. Recently, HOXB13 has been established as the first validated prostate cancer susceptibility gene. Among the HOXB13 germline mutations discovered in hereditary prostate cancer, the p.Gly84Glu mutation (G84E) is consistently associated with increased prostate cancer risk. The mechanism behind such association remains elusive. This study aims to test the hypothesis that HOXB13 is a proto-oncogene with activating mutations in prostate cancer. Herein, HOXB13 expression in normal and malignant prostate cells was characterized using qPCR, immunoblot and IHC analyses. Given the clustering of HOXB13 mutations to the purported MEIS binding domains, HOXB13-MEIS interaction was examined with co-IP assays. Finally, to interrogate the transforming capacity of HOXB13, normal prostate cell models were lentivirally engineered to express HOXB13. Novel findings include discovery of an alternative form of HOXB13 located in the cytoplasm of normal prostatic cells, a HOXB13-MEIS1 interaction which functions in regulation of gene expression and cytokeratin 14 as a major transcriptional target of HOXB13 in prostate basal epithelial cells. Additionally, various molecular aspects such as subcellular localization, protein half-life and MEIS interaction have been largely ruled out as G84E-induced alterations in HOXB13, although more subtle differences may exist. In total, this thesis has uncovered and characterized novel aspects of HOXB13 expression, regulation and interaction with cofactors in the prostate, promising avenues for further research aimed at fully elucidating HOXB13 function in normal prostate and prostate cancer biology