Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer

Comprehensive Drug Testing of Patient-derived Conditionally Reprogrammed Cells from Castration-resistant Prostate Cancer

Background Technology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa. Objective We established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs. Design, setting, and participants CRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling. Outcome measurements and statistical analysis The phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language. Results and limitations We generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids. Conclusions Comprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC. Patient summary We describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.Peer reviewe

The Alternative Splice Variant of Protein Tyrosine Kinase 6 Negatively Regulates Growth and Enhances PTK6-Mediated Inhibition of β-Catenin

Protein tyrosine kinase 6 (PTK6), also called breast tumor kinase (BRK), is expressed in epithelial cells of various tissues including the prostate. Previously it was shown that PTK6 is localized to epithelial cell nuclei in normal prostate, but becomes cytoplasmic in human prostate tumors. PTK6 is also primarily cytoplasmic in the PC3 prostate adenocarcinoma cell line. Sequencing revealed expression of wild type full-length PTK6 transcripts in addition to an alternative transcript lacking exon 2 in PC3 cells. The alternative transcript encodes a 134 amino acid protein, referred to here as ALT-PTK6, which shares the first 77 amino acid residues including the SH3 domain with full length PTK6. RT-PCR was used to show that ALT-PTK6 is coexpressed with full length PTK6 in established human prostate and colon cell lines, as well as in primary cell lines derived from human prostate tissue and tumors. Although interaction between full-length PTK6 and ALT-PTK6 was not detected, ALT-PTK6 associates with the known PTK6 substrates Sam68 and β-catenin in GST pull-down assays. Coexpression of PTK6 and ALT-PTK6 led to suppression of PTK6 activity and reduced association of PTK6 with tyrosine phosphorylated proteins. While ALT-PTK6 alone did not influence β-catenin/TCF transcriptional activity in a luciferase reporter assay, it enhanced PTK6-mediated inhibition of β-catenin/TCF transcription by promoting PTK6 nuclear functions. Ectopic expression of ALT-PTK6 led to reduced expression of the β-catenin/TCF targets Cyclin D1 and c-Myc in PC3 cells. Expression of tetracycline-inducible ALT-PTK6 blocked the proliferation and colony formation of PC3 cells. Our findings suggest that ALT-PTK6 is able to negatively regulate growth and modulate PTK6 activity, protein-protein associations and/or subcellular localization. Fully understanding functions of ALT-PTK6 and its impact on PTK6 signaling will be critical for development of therapeutic strategies that target PTK6 in cancer

Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with 35S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases

Serum Vitamin D and Risk of Prostate Cancer in a Case-Control Analysis Nested Within the European Prospective Investigation into Cancer and Nutrition (EPIC)

Results from the majority of studies show little association between circulating concentrations of vitamin D and prostate cancer risk, a finding that has not been demonstrated in a wider European population, however. The authors examined whether vitamin D concentrations were associated with prostate cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (1994–2000). Serum concentrations of 25-hydroxyvitamin D were measured in 652 prostate cancer cases matched to 752 controls from 7 European countries after a median follow-up time of 4.1 years. Conditional logistic regression models were used to calculate odds ratios for prostate cancer risk in relation to serum 25-hydroxyvitamin D after standardizing for month of blood collection and adjusting for covariates. No significant association was found between 25-hydroxyvitamin D and risk of prostate cancer (highest vs. lowest quintile: odds ratio = 1.28, 95% confidence interval: 0.88, 1.88; P for trend = 0.188). Subgroup analyses showed no significant heterogeneity by cancer stage or grade, age at diagnosis, body mass index, time from blood collection to diagnosis, or calcium intake. In summary, the results of this large nested case-control study provide no evidence in support of a protective effect of circulating concentrations of vitamin D on the risk of prostate cancer

Increased CK5/CK8-Positive Intermediate Cells with Stromal Smooth Muscle Cell Atrophy in the Mice Lacking Prostate Epithelial Androgen Receptor

Results from tissue recombination experiments documented well that stromal androgen receptor (AR) plays essential roles in prostate development, but epithelial AR has little roles in prostate development. Using cell specific knockout AR strategy, we generated pes-ARKO mouse with knock out of AR only in the prostate epithelial cells and demonstrated that epithelial AR might also play important roles in the development of prostate gland. We found mice lacking the prostate epithelial AR have increased apoptosis in epithelial CK8-positive luminal cells and increased proliferation in epithelial CK5-positive basal cells. The consequences of these two contrasting results could then lead to the expansion of CK5/CK8-positive intermediate cells, accompanied by stromal atrophy and impaired ductal morphogenesis. Molecular mechanism dissection found AR target gene, TGF-β1, might play important roles in this epithelial AR-to-stromal morphogenesis modulation. Collectively, these results provided novel information relevant to epithelial AR functions in epithelial-stromal interactions during the development of normal prostate, and suggested AR could also function as suppressor in selective cells within prostate

Expression of androgen receptor and prostate-specific antigen in male breast carcinoma

BACKGROUND: The androgen-regulated proteins prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) are present in high concentrations in normal prostate and prostatic cancer and are considered to be tissue-specific to prostate. These markers are commonly used to diagnose metastatic prostate carcinoma at various sites including the male breast. However, expression of these two proteins in tumors arising in tissues regulated by androgens such as male breast carcinoma has not been thoroughly evaluated. METHODS: In this study we analyzed the expression of PSA, PSAP and androgen receptor (AR) by immunohistochemistry in 26 cases of male breast carcinomas and correlated these with the expression of other prognostic markers. RESULTS: AR, PSA and PSAP expression was observed in 81%, 23% and 0% of carcinomas, respectively. Combined expression of AR and PSA was observed in only four tumors. CONCLUSION: Although the biological significance of PSA expression in male breast carcinomas is not clear, caution should be exercised when it is used as a diagnostic marker of metastatic prostate carcinoma