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1.  Germline Mutations in HOXB13 and Prostate-Cancer Risk 
The New England journal of medicine  2012;366(2):141-149.
BACKGROUND
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.
METHODS
We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.
RESULTS
Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10−7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10−6).
CONCLUSIONS
The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)
doi:10.1056/NEJMoa1110000
PMCID: PMC3779870  PMID: 22236224
2.  Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status 
Cytokines may play a role in the initiation and progression of prostate cancer. A cytokine antibody array was previously applied to prostatic fluid obtained from patients with prostate cancer, and interleukin 18 binding protein (IL-18BP), a potent inhibitor of interleukin 18, was noted to be significantly upregulated in cases with large volume disease. We sought to further characterize the association of IL-18BP with prostate cancer and determine whether IL-18BP levels in patient serum and urine samples had clinical relevance. IL-18BP was expressed and secreted by the prostate cancer cell lines DU145 and PC3, but not by LNCaP and CWR22, upon interferon-γ (IFN-γ) stimulation. IFN-γ-induced secretion of IL-18BP was enhanced by added TNF-α, IFN-α and IFN-β. The IL-18BP secreted from DU145 and PC3 functionally inhibited IL-18. Immunohistochemical analyses showed positive IL-18BP staining in prostate cancer cells as well as in macrophages in radical prostatectomy specimens. Significant differences in urinary IL-18BP levels (normalized by total protein) collected post-DRE were found between cases with and without cancer on biopsy (P = 0.02) and serum IL-18BP levels correlated with Gleason score (P = 0.03). Our finding of elevated IL-18BP secretion from prostate cancer cells suggests an attempt by cancer to escape immune surveillance. IL-18BP merits further study as a marker of aggressive prostate cancer and as a therapeutic target.
doi:10.1002/ijc.25705
PMCID: PMC3040782  PMID: 20878981
Prostate cancer; IL-18 binding protein; urinary marker
4.  α-catenin overrides Src-dependent activation of β-catenin oncogenic signaling 
Molecular cancer therapeutics  2008;7(6):1386-1397.
Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α, β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating β-catenin’s cell-cell adhesion and proliferation functions. In α-catenin null prostate cancer cells, re-expression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin null cells. α-catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.
doi:10.1158/1535-7163.MCT-07-2029
PMCID: PMC2527861  PMID: 18566211
catenin; prostate cancer; adherens junction; src; TCF/LEF
5.  Endoglin (CD105) as a Urinary and Serum Marker of Prostate Cancer 
We have previously shown that endoglin (CD105) is upregulated in prostatic fluid of men with large volume prostate cancer. We chose to assess endoglin levels in urine and serum from men with prostate cancer or at increased risk for the disease: Urine samples were collected after DRE from 99 men whose cancer status was confirmed by biopsy, and serum samples were collected from 20 men without prostate cancer at low risk for the disease, and from 69 men diagnosed with prostate cancer that subsequently underwent radical prostatectomy (30 pT2, 39 pT3). Endoglin levels were assessed by ELISA. Urinary endoglin was elevated in men with biopsy-positive prostate cancer compared to biopsy-negative men (p=0.0014). Urinary endoglin levels in men with prostate cancer correlated with radical prostatectomy tumor volume. The area under the receiver-operator characteristics (ROC) curve was 0.72 for urinary endoglin and 0.50 for serum prostate-specific antigen PSA (sensitivity for cancer detection 73%, specificity 63%). There were no differences in serum endoglin between normal and cancer cases, but there were increases in serum endoglin in non-organ confined (NOC, pT3+) vs. organ-confined (OC, pT2) cases (p=0.0004). The area under the ROC curve was 0.75 for serum endoglin and 0.63 for PSA for predicting NOC status, with a sensitivity of 67% and a specificity of 80%. In conclusion, elevations in post-DRE urinary endoglin suggest there may be value in further studying endoglin as a urinary biomarker of prostate cancer. Endoglin levels in both urine and serum may aid in prostate cancer detection and prognostication.
doi:10.1002/ijc.24007
PMCID: PMC2666305  PMID: 19004009
Endoglin; CD105; Prostate Cancer; Biological Markers; Clinical Markers
6.  Cytokine Profiling of Prostatic Fluid from Cancerous Prostate Glands 
The Prostate  2008;68(8):872-882.
BACKGROUND
Cytokines are key mediators of inflammation that may play important roles in prostate cancer initiation and progression. Cytokines found in cancerous prostates may provide further insight into the mechanisms of cancer initiation and progression, and facilitate the exploration of new markers of prostatic neoplasia and inflammation. We describe the cytokine profile of prostatic fluids obtained from cancerous prostate glands and correlate it to both cancer status and inflammation grade.
METHODS
Prostatic fluid was collected from fresh radical prostatectomy specimens and analyzed by human cytokine antibody microarray. Cases were selected from patients with either minimal or extensive cancer volume on final pathology. Among the cytokines with the greatest difference between the tumor volume groups, eight had their levels quantitated by ELISA and correlated with cancer status and grade of inflammation by neutrophils, macrophages and lymphocytes.
RESULTS
Among 174 cytokines analyzed, HGF was the most increased (6.57-fold), and HGF and IL18Bpa were significantly elevated in patients with extensive prostate cancer. IL17, GITR, ICAM-1, and IL-18Bpa were elevated in specimens with neutrophilic inflammation into gland lumina, and IL18Bpa, IL17, GITR, ICAM-1 were elevated in specimens with lymphocytic inflammation in prostatic stroma.
CONCLUSIONS
Prostatic fluid cytokines were identified that may be useful in early detection and prognostication efforts for prostate cancer, particularly if they can be found not only in prostatic fluids obtained ex vivo, but in expressed prostatic secretions or urine samples from patients with their prostates still in situ.
doi:10.1002/pros.20755
PMCID: PMC2562260  PMID: 18361406
cancer; inflammation; cytokine
7.  Homozygous Deletions and Recurrent Amplifications Implicate New Genes Involved in Prostate Cancer12 
Neoplasia (New York, N.Y.)  2008;10(8):897-907.
Prostate cancer cell lines provide ideal in vitro systems for the identification and analysis of prostate tumor suppressors and oncogenes. A detailed characterization of the architecture of prostate cancer cell line genomes would facilitate the study of precise roles of various genes in prostate tumorigenesis in general. To contribute to such a characterization, we used the GeneChip 500K single nucleotide polymorphic (SNP) array for analysis of genotypes and relative DNA copy number changes across the genome of 11 cell lines derived from both normal and cancerous prostate tissues. For comparison purposes, we also examined the alterations observed in the cell lines in tumor/normal pairs of clinical samples from 72 patients. Along with genome-wide maps of DNA copy number changes and loss of heterozygosity for these cell lines, we report previously unreported homozygous deletions and recurrent amplifications in prostate cancers in this study. The homozygous deletions affected a number of biologically important genes, including PPP2R2A and BNIP3L identified in this study and CDKN2A/CDKN2B reported previously. Although most amplified genomic regions tended to be large, amplifications at 8q24.21 were of particular interest because the affected regions are relatively small, are found in multiple cell lines, are located near MYC, an oncogene strongly implicated in prostate tumorigenesis, and are known to harbor SNPs that are associated with inherited susceptibility for prostate cancer. The genomic alterations revealed in this study provide an important catalog of positional information relevant to efforts aimed at deciphering the molecular genetic basis of prostate cancer.
PMCID: PMC2481576  PMID: 18670647

Results 1-7 (7)