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Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 ( SLCO1B3 ). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 ( K m = 23.2 μmol/L; V max = 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 (-/-) mice, Slco1b2 (-/-)/ hSLCO1B3 knockins had greater hepatic uptake (15% greater AUC, P = 0.0040) and lower plasma exposure to 3H-testosterone (17% lower AUC, P = 0.0030). Of 82 transporters genes, SLCO1B3 is the second-most differentially expressed transporter in CRPC cell lines (116-fold vs. androgen-sensitive cells), with a differentially spliced cancer-type ct- SLCO1B3 making up the majority of SLCO1B3 expression. Overexpression of SLCO1B3 in androgen-responsive cells results in 1.5- to 2-fold greater testosterone uptake, whereas siRNA knockdown of SLCO1B3 in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors express SLCO1B3 to a greater extent than ct-SLCO1B3 (26% of total SLCO1B3 expression vs. 0.08%), suggesting that androgen uptake in these tumor cells also is greater. Non-liver tumors do not differentially express SLCO1B3. Implications: This study suggests that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Mol Cancer Res; 15(8); 1096-105. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment., Methods: A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations., Results: There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk., Conclusions: Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Objective: To assess the significance of viable tumour in the prostate of patients with metastatic androgen-independent prostate cancer (AIPC)., Patients and Methods: We evaluated the clinicopathological features, including follow-up, of 40 men with metastatic AIPC who had a transrectal biopsy of the prostate., Results: Prostate biopsies (median three cores per biopsy) showed viable tumour in 19 of 40 patients (48%). Of the 18 patients who had received radiotherapy (RT), nine had negative on-study biopsy results. A previous history of RT was not associated with overall survival in patients with biopsy-positive tumours (P = 0.84). Also, there was no statistically significant association between positive or negative biopsy status and overall survival (OS) in these 40 patients (P = 0.39), with a similar median OS of 19.6 months for biopsy-negative and 19.8 months for biopsy-positive patients, respectively., Conclusions: Taking prostate biopsies at the time of documented metastatic AIPC yielded tumour in about half the patients. A previous history of RT was not associated with a negative prostate biopsy; the latter appears to have no influence on the prognosis.

The conversion from E-cadherin to N-cadherin has been observed in several human cancer types, including prostate cancer, with more homogenous expression of N-cadherin detected in high-grade prostate tumors. N-cadherin, in vitro, has been shown to promote cell mobility, migration and invasion of several cancer cell lines, indicating the possibility of N-cadherin as a molecular target of cancer therapy. Herein, we examined the potential of an N-cadherin inhibitor, ADH1, in reducing tumor angiogenesis ex vivo and delaying tumor progression in vivo. Our data demonstrate that ADH1, at the dosages evaluated, does not display either antiangiogenic activity in a rat aortic ring assay or antitumor potential in a PC3 subcutaneous xenograft tumor model. We detected cytotoxic activity in human umbilical vein endothelial cells, PC3, and Tsu-Pr1 cells, when ADH1 exposure was evaluated at 500 micromol/l or above.

The hypoxia-inducible factor 1alpha (HIF-1alpha) plays a major role in cancer progression. The role of this transcription factor in prostate cancer development and its transition to a metastatic and androgen refractory state remains to be elucidated. Previous reports have identified the existence of single nucleotide polymorphisms (SNPs) in the oxygen-dependent degradation domain of the HIF-1alpha gene in renal cell carcinoma, head and neck squamous cell carcinoma, and androgen-independent prostate cancer (AIPC). Studies in prostate cancer, however, are variable and limited in the number of cases assessed. Herein we further investigate these SNPs, specifically C1772T (which results in an amino acid change from proline 582 to serine) and G1790A (alanine 588 to threonine). The frequency of these polymorphisms was evaluated in a population of individuals with metastatic AIPC and compared to a set of healthy control subjects. The distribution of HIF-1alpha genotypes for C1772T in 196 AIPC patients was 161 C/C (82.1%), 29 C/T (14.8%), and 6 T/T (3.1%). The genotype distribution in 196 controls was 179 C/C (91.3%), 14 C/T (7.1%), and 3 T/T (1.5%). Our results demonstrate a significant difference in genotype distribution between AIPC patients and control subjects only for the C1772T polymorphism (p = 0.024). The association of the incidence of the polymorphism with overall survival was determined to be not statistically significant (p = 0.93) by the Mantel-Haenszel (log-rank) test. These results suggest that the C1772T polymorphism in HIF-1alpha may confer susceptibility to AIPC and contribute to the progression or metastasis of this disease.

Purpose: After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen-independent cancer. The molecular mechanisms underlying progression are not well known in part due to the rarity of androgen-independent samples from primary and metastatic sites., Experimental Design: We compared the gene expression profiles of 10 androgen-independent primary prostate tumor biopsies with 10 primary, untreated androgen-dependent tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A GeneChip. Differential expression was examined with principal component analysis, hierarchical clustering, and Student's t testing. Analysis of gene ontology was done with Expression Analysis Systematic Explorer and gene expression data were integrated with genomic alterations with Differential Gene Locus Mapping., Results: Unsupervised principal component analysis showed that the androgen-dependent and androgen-independent tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between androgen-independent and androgen-dependent tumors: macromolecule biosynthesis was down-regulated and cell adhesion was up-regulated in androgen-independent tumors. Other differentially expressed genes were related to interleukin-6 signaling as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The Differential Gene Locus Mapping analysis identified nine regions of potential chromosomal deletion in the androgen-independent tumors, including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21., Conclusions: Taken together, these data identify several unique characteristics of androgen-independent prostate cancer that may hold potential for the development of targeted therapeutic intervention.

Androgens are of primary importance in the etiology of prostate cancer, and binding of the androgen dihydrotestosterone to the androgen receptor is thought to stimulate prostate growth. It has been proposed that polymorphisms within key androgen regulatory genes may contribute to an individual's risk of developing prostate cancer. Attributing single polymorphisms to complex, late-onset, chronic diseases such as prostate cancer is probably not feasible, but identification of genes that increase risk will contribute to larger-scale multigenic risk assessment. Here, we review the current status of our knowledge of associations between important androgen regulatory gene polymorphisms and prostate cancer risk.

Purpose: We investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer. Materials and Methods: This is a nested case-control study of 1,159 cases and 1,353 controls from the Prostate Cancer Prevention Trial, a randomized, placebo controlled trial testing whether the 5α-reductase inhibitor finasteride could decrease the 7-year prevalence of prostate cancer. During the course of the trial men underwent annual digital rectal examination and prostate specific antigen measurement. Prostate biopsy was recommended in all men with abnormal digital rectal examination or finasteride adjusted prostate specific antigen greater than 4.0 ng/ml. Cases were drawn from men with biopsy determined prostate cancer identified by for cause or end of study biopsy. Controls were selected from men who completed the end of study biopsy. Results: Mean CAG repeat length did not differ between cases and controls. The frequency distribution of cases and controls for the AR CAG repeat length was similar. There were no significant associations of CAG repeat length with prostate cancer risk when stratified by treatment arm (finasteride or placebo), or when combined. There was also no significant association between CAG repeat length and the risk of low or high grade prostate cancer. Conclusions: There is no association of AR CAG repeat length with prostate cancer risk. Knowledge of AR CAG repeat length provides no clinically useful information to predict prostate cancer risk. [Copyright &y& Elsevier]

OBJECTIVE To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. PATIENTS AND METHODS We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). RESULTS When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 ( P = 0.11) and D2 ( P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele ( P = 0.048). CONCLUSION A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT. [ABSTRACT FROM AUTHOR]

The androgen receptor plays a major role in the development and function of normal and malignant prostate cells. Due to the relationship of the androgen receptor and prostatic growth, it has been proposed that polymorphisms within the androgen receptor may play a role in an individual’s susceptibility to developing prostate cancer. An inverse relationship has been established between a highly polymorphic trinucleotide repeat located in the first exon of the androgen receptor and the transactivaton function of the receptor. Serum samples were collected from 131 patients with histologically confirmed adenocarcinoma of the prostate, DNA was isolated, and the polymorphic CAG repeat was amplified by PCR and sequenced. The CAG repeat lengths were then compared with age at diagnosis, age at time of study, baseline log[sub 10] PSA, Gleason score, time from diagnosis to initiation of hormonal therapy, time to progression after androgen ablation, and overall survival time. No correlation was found between CAG length and time to progression or overall survival time, but a significant correlation was found between Gleason score and CAG length suggesting that shorter CAG lengths may predict a higher histological grade of prostate cancer.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between a cytochrome P450 17alpha-hydroxylase gene (CYP17) polymorphism and survival in Caucasian patients with androgen-independent prostate cancer (AIPC).Methods: The study used 222 samples acquired from Caucasian patients with AIPC. The CYP17 polymorphism (-34T>C) was analyzed using polymerase chain reaction amplification followed by restriction fragment length polymorphism detection.Results: No significant differences were observed in the frequencies of the CYP17 genotype in relation to categorized Gleason scores, age at diagnosis, or hormone therapy. The median survival was significantly longer in 126 patients with the CYP17 A2 allele (8.9 years) genotype than in 96 patients with the A1 allele (6.7 years) genotype (P = 0.040 by log-rank test). Similarly, the estimated survival probability at 10 years (24% in A1 allele versus 43% in A2 allele) showed a statistically significant difference between the two groups (P = 0.002 by the permutation test).Conclusions: These results suggest that the CYP17 polymorphism is associated with overall survival in patients with AIPC. [ABSTRACT FROM AUTHOR]