Aggressive Forms Of Prostate Cancer Research Articles

Expression Profiling of Hereditary versus Sporadic Prostate Cancer Suggests CYR61, EGR3, KLF6 and SNF1LK as Differentially Expressed Genes

Background: Distinguishing between sub-clinical and aggressive forms of prostate cancer is difficult due to the heterogeneity of the disease. It is, however, important to identify aggressive forms to guide proper treatment. This study compared gene expression profiles in cancer cells from hereditary and sporadic prostate cancer cases and attempted to correlate differentially regulated genes with clinico-pathological characteristics and prognosis. Materials and methods: The study population comprised patients diagnosed with clinically localized prostate cancer undergoing prostatectomy. Patients were divided into hereditary and sporadic cancer cases based on their family history. Fresh frozen biopsies from prostatectomy specimens were laser-dissected for RNA-extraction. Affymetrix HG-U133 Plus GeneChips were used to measure gene expression loaded onto Cluster 3.0 and Ingenuity Pathway Analysis softwares to examine the relationship among genes between groups. Differentially expressed genes were selected for protein expression analysis using immunohistochemistry on histological sections and tissue microarrays. Results: No single genes were signifycantly differentially expressed between hereditary and sporadic cases after adjustment for multiple testing. Using cluster analysis, four transcripts were found to be upregulated in hereditary prostate cancer tissue: CYR61, EGR3, KLF6 and SNF1LK. The intensity of CYR61, EGR2, KLF6 and SNF1LK immunostainings, however, were not significantly different in a separate sample of hereditary and sporadic prostate cancers. Furthermore, no correlations between CYR61, EGR2, KLF6, and SNF1LK staining intensities and the clinico-pathological variables or disease-free survival were detected, except for EGR3 that was significantly associated with T stage (p = 0.04). Conclusion: Overall, no single transcript level was significantly associated with hereditary prostate cancer. Cluster analysis suggested that the expression of CYR61, EGR3, KLF6 and SNF1LK were upregulated in cancer tissue from hereditary cases, but we were not able to confirm this on the protein level, and levels of these proteins were not found to correlate with clinico-pathological characteristics or biochemical recurrence.

New variants at 10q26 and 15q21 are associated with aggressive prostate cancer in a genome-wide association study from a prostate biopsy screening cohort

Purpose: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort. Experimental Design: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer. Results: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10−10 to 3.2 × 10−11) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10−8 to 8.2 × 10−9) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8–3.0, p value 0.003–0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk. Conclusions: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.

Abstract C7: Analysis of high-risk prostate cancer markers at RNA and protein level.

Abstract Background: In many developed countries, prostate cancer is the second leading cause of cancer-related deaths among men. Current diagnostic possibilities do not differentiate aggressive forms of prostate cancer from latent tumors. Therefore, having reliable and easy-to-detect marker is needed to treat this disease successfully. We determined potential novel tumor markers of high-risk prostate cancer (A) at the cell level, represented by cell lines 22Rv1 and PNT1A and (B) in the serum of 82 histologicaly -verified cases and 51 controls. Material and Methods: 22Rv1 cell line derived from primary prostate tumor and PNT1A cell line derived from normal prostate epithelium were used in our study. The real time PCR, electrophoretical separation technique, immunochemical detection and novel electrochemical analysis were used in tumor markers determination. Findings and Interpretation: Cell line 22Rv1 represents Gleason sum 9 primary tumor, compared to widely used cell lines PC-3, LNCaP and PD-145, representing metastasis, therefore, is more related to real tumor tissue. We determined RNA and protein level of genes alpha-methyl acyl-CoA racemase (AMACR), caveolin-1, metalothionein, p53, NF-kB, FOS, JUN, Ki-67, ZIP1 and ZnT-1. At the RNA level in cell lines we found significant (p < 0.01) down-regulation of Cav-1 (50-fold), NF-kB (11-fold) and others and significant (p < 0.01) up-regulation of metalothionein (2.4-fold), AMACR (8.4-fold), Ki-67 (2-fold) and zinc transporters ZnT-1 (25-fold) and ZIP1 (45-fold). Conversely, we observed down-regulation of metallothionein at protein level. In the serum of prostate cancer patients we found no significant differences in AMACR and caveolin-1 level and significantly (p < 0.001) higher metallothionein level suggesting metalothionein as a complementary marker to PSA. We found weak correlation of PSA on caveolin-1 (r = 0.41 at p = 0.002) and, interestingly, significant elevation of caveolin-1 in high-grade tumors (tumor stage 4 (2.3-fold elevation), Gleason sum 9, correlation at r = 0,29 at p = 0,028) suggesting caveolin-1 as potential high-risk prostate cancer marker. This study provides important new information about selected genes connected with prostate cancer and describes new electrochemical approaches for their determination in lower concentrations. Financial support from IGA MH of Czech republic no. NS10200–3 is greatly acknowledged. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C7.

The natural product CCR5 antagonist anibamine and its analogs as anti-prostate cancer agents

Prostate cancer is a leading cause of death among males in the United States. As the chemokine receptor CCR5 is over-expressed in more aggressive forms of prostate cancer, and is also a critical receptor in inflammation, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. Anibamine, a natural product CCR5 antagonist, provides a unique molecular scaffold for the generation of novel analogs with possible anti-prostate cancer activity. A series of analogs of anibamine were designed, synthesized and tested against several prostate cancer cell lines. The analogs all acted as CCR5 antagonists at micromolar range affinity to the receptor while their anti-proliferative activity varied depending on the cell line type and their chemical structural properties. Further basal cytotoxicity characterization on these compounds indicated some of them may be suitable for in vivo studies.

The role of nuclear endothelial nitric oxide synthase in the endothelial and prostate microenvironments.

This review is based on novel observations from our laboratory on the nuclear translocation and functional role of endothelial nitric oxide synthase (eNOS) in endothelial and prostate cancer (PCa) epithelial cells. Nitric oxide (NO), the product of eNOS, is a free radical involved in the physiology and pathophysiology of living organisms and in a variety of biological processes including the maintenance of vascular homeostasis. Of relevance in this context is the role that estrogens play in the apoptotic process and the migration of endothelial cells through the regulation of target genes such as eNOS itself. It has been shown that both estrogen and NO signaling, mediated respectively by the estrogen receptors (ERs) and eNOS, can strongly counteract endothelial senescence through a common effector, the catalytic subunit of human telomerase. Therefore, this protein has been identified as a key molecule in the aging process which, intriguingly, is considered the only risk factor in the development of PCa and one of the major determinants of cardiovascular diseases. Indeed, in both these contexts we have defined a molecular mechanism involving activation of eNOS and hypoxia-inducible factors in association with ERβ that characterizes the most aggressive form of PCa or influences endothelial cell differentiation. Altogether these data led us to postulate that activation of eNOS is a crucial requirement for the delaying of endothelial senescence as well as for the acquisition of androgen-independence and for tumor progression in the prostate microenvironment.

The Siah2-HIF-FoxA2 axis in prostate cancer - new markers and therapeutic opportunities

Recent studies indicate the importance of the ubiquitin ligase Siah2 in control of more aggressive prostate tumors – namely, neuroendocrine (NE) prostate tumors and prostate adenocarcinoma (PCa) harboring neuroendocrine lesions. Siah2-dependent expression and activity of HIF-1α regulate its availability to form a transcriptional complex with FoxA2, resulting in expression of specific target genes, including Hes6, Sox9 and Jmjd1a, whose co-expression is sufficient for formation of NE tumors and NE lesions in PCa. These studies provide novel markers to diagnose and monitor formation of NE lesions and NE tumors. Furthermore, defining the regulatory axis consisting of Siah2 and HIF-1α/FoxA2 cooperation suggests novel therapeutic modalities to treat these most aggressive forms of prostate cancer. Here we review current understanding of Siah role in control of hypoxia and prostate tumor development and highlight potential approaches for targeting components along Siah-regulated pathways.

Vitamin D pathway gene variants and prostate cancer prognosis

Observational studies linking vitamin D deficiency with increased prostate cancer (PCa) mortality and the pleiotropic anticancer effects of vitamin D in malignant prostate cell lines have initiated trials examining potential therapeutic benefits of vitamin D metabolites. There have been some successes but efforts have been hindered by risk of inducing hypercalcemia. A limited number of studies have investigated associations between variants in vitamin D pathway genes with aggressive forms of PCa. Increased understanding of relevant germline genetic variation with disease outcome could aid in the development of vitamin-D-based therapies. We undertook a comprehensive analysis of 48 tagging single-nucleotide polymorphisms (tagSNPs) in genes encoding for vitamin D receptor (VDR), vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) in a cohort of 1,294 Caucasian cases with an average of 8 years of follow-up. Disease recurrence/progression and PCa-specific mortality risks were estimated using adjusted Cox proportional hazards regression. There were 139 cases with recurrence/progression events and 57 cases who died of PCa. Significantly altered risks of recurrence/progression were observed in relation to genotype for two VDR tagSNPs (rs6823 and rs2071358) and two CYP24A1 tagSNPs (rs927650 and rs2762939). Three VDR tagSNPs (rs3782905, rs7299460, and rs11168314), one CYP27B1 tagSNP (rs3782130), and five CYP24A1 tagSNPs (rs3787557, rs4809960, rs2296241, rs2585428, and rs6022999) significantly altered risks of PCa death. Genetic variations in vitamin D pathway genes were found to alter both risk of recurrence/progression and PCa-specific mortality.

Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor

Background: Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men with high levels of serum calcium. Because serum calcium levels are influenced by the calcium-sensing receptor (CaSR), we examined prostate cancer in African American men in relation to three single nucleotide polymorphisms (SNPs) in the CaSR gene, A986S, R990G, and Q1011E. This is the first study of CaSR polymorphisms and risk of prostate cancerMethods: We genotyped three CaSR SNPs for 458 African American prostate cancer cases and 248 controls from a population-based case-control study, the California Collaborative Prostate Cancer Study.Results: The CaSR genotypes were not associated with prostate cancer overall. However, we observed significant heterogeneity by disease stage for the Q1011E polymorphism (p=0.02). Advanced cases were significantly less likely than controls or localized cases to be homozygous for the minor allele of the Q1011E polymorphism (1% vs. 5%). Cases with advanced disease were six times less likely to carry two copies of the minor allele than were controls (OR=0.16, p=0.02) or localized cases (OR=0.15, p=0.01) and were significantly older at diagnosis (68.8 ±5.7 vs. 64.0 ± 9.0 years for the QQ and EE genotypes, p = 0.004).Conclusions: The CaSR Q1011E minor allele, which is common in populations with African ancestry, may be associated with a less aggressive form of prostate cancer among African American men.

Next generation RNA sequencing of neuroendocrine prostate cancer.

e15010 Background: Neuroendocrine prostate cancer (NEPC) represents a distinct, aggressive form of prostate cancer that may present de novo or following hormonal treatment of prostate adenocarcinoma (PCa). Despite aggressive chemotherapy, most patients die within a year. We used expression profiling to identify genetic alterations in NEPC and nominate therapeutic candidates. Methods: We performed massively parallel paired-end RNA sequencing (RNA-Seq) using the Illumina Genome Analyzer II. We employed a Bioinformatics approach to quantify gene expression, evaluate point mutations, and utilized a novel computational tool (FusionSeq) to identify gene fusions (archive.gersteinlab.org/proj/rnaseq/fusionseq). Connectivity Mapping (CMAP), a program to correlate expression data with gene expression of cells treated with 1309 small molecules (broadinstitute.org/cmap), was used to nominate compounds that reverse the NEPC gene signature. Results: 7 NEPCs were evaluated, with 3 being pure NEPC and 4 mixed with PCa. 65-125 million paired-end reads were obtained (52-61% mappable to reference genome). 9 highly ranked gene fusions were detected, including TMPRSS2-ERG in 1/7 cases. 28% of known genes showed significant gene expression differences compared to 51 PCa reference cases (Benjamini- Hochberg correction p <0.05). Neuroendocrine genes (CGHA, CGHB, S100) were high, androgen regulated genes (PSA, TMPRSS2, NKX3.1) and AR were low, and EZH2, MIB1, SYP were differentially expressed in NEPC versus PCa, with exception of the TMPRSS2-ERG NEPC case which showed a pattern similar to PCa. Several kinases implicated in cancer were upregulated in NEPC (AURKA, AURKB, CDK2, TYK2). CMAP nominated drug candidates, including known chemotherapeutic agents (etoposide), HDAC inhibitors (vorinostat), the red wine derivative resveratrol, and SERM raloxifene. Conclusions: RNA-Seq detected significant genetic differences between NEPC and PCa. The NEPC case that resembles PCa on a molecular level may represent a significant intermediate subtype. Ongoing RNA-Seq analysis, including pathway and mutation analyses, will help identify driving lesions. Overexpression of kinases may represent previously unknown targets for therapeutic intervention. No significant financial relationships to disclose.

Common sexual infection linked to aggressive prostate cancer

Researchers have found a strong association between a common sexually transmitted infection and an aggressive form of prostate cancer. The study, conducted by researchers at the Harvard School of Public Health and Brigham and Women's Hospital, both in Boston, Massachusetts,was published in the Journal of the National Cancer Institute.1 The infection, known as Trichomonas vaginalis, infects an estimated 174 million people globally each year and can cause inflammation of the prostate. Men may not realize they are infected because they may not have any symptoms. Prostate inflammation appears to play an important role in the development and progression of prostate cancer. In the study, T vaginalis was found to be associated with a greater than 2-fold increase in the risk of prostate cancer that was advanced at the time of diagnosis and a nearly 3-fold increase in prostate cancer that would lead to death. Researchers analyzed blood samples from 673 patients with prostate cancer from the Physicians' Health Study. They compared their infection status with that of 673 men who had not been diagnosed with the disease. The samples were collected approximately 10 years before the men were diagnosed. Further research is needed to confirm the findings. If they are confirmed, however, the infection, which is easily treated with antibiotics,may be 1 of the few known, potentially modifiable risk factors for aggressive prostate cancer, the authors note.

Chronic Fatigue and Prostate Cancer: A Retroviral Connection?

As if chronic fatigue syndrome (CFS) hasn't caused enough brawls, a new study published online by Science links the disease to a possibly contagious rodent retrovirus, XMRV, which has also been implicated in an aggressive form of prostate cancer.

How notorious do dying prisoners need to be to receive high quality end-of-life care?

The release from a Scottish prison in August this year of the Lockerbie bomber, Abdelbaset Ali al-Megrahi, caused outrage and condemnation across the world, with the President of the USA, Barack Obama, voicing his disappointment directly to UK Prime Minister Gordon Brown. Al-Megrahi was released on compassionate grounds after being diagnosed with an aggressive form of prostate cancer, having served 8 years of a 27-year sentence for blowing up PanAm Flight 103 and killing 270 people in 1988. In another recent high profile case, the notorious ‘great train robber’, Ronnie Biggs, was also granted compassionate release from a British prison in August. Biggs, now 80 years old, has had several strokes, and at the time of his release was suffering from pneumonia and not expected to survive.

Common variants in 8q24 are associated with risk for prostate cancer and tumor aggressiveness in men of European ancestry

Recent whole genome association studies have independently identified multiple prostate cancer (PC) risk variants on 8q24. We have evaluated association of common variants in this region with PC susceptibility and tumor aggressiveness in a sample of European American men. Forty-nine tagging SNPs including three previously reported significant variants (rs1447295, rs6983267, rs16901979) and seven variants in the 5' upstream region of the MYC proto-oncogene were tested for association with susceptibility to PC and tumor aggressiveness in 596 histologically verified PC cases and 567 ethnically matched controls. Significant associations with susceptibility to PC were found at 17 SNPs, four of which (rs1016342, rs1378897, rs871135, and rs6470517) remained significant after adjusting for multiple corrections. One of the associated SNPs, rs871135, is located in the putative gene POU5F1P1 within the 8q24 region. An in slico analysis showed that the associated variant of this SNP alters a transcription factor implicating a plausible regulatory role. Additionally, one of the significantly associated SNPs, rs6470517, with PC susceptibility showed a significant over-representation of the G allele in cases with aggressive tumor. Although this study does not directly confirm associations of the three specific SNPs (cited above), it corroborates reported signals of association in 8q24 reaffirming that genetic variation on 8q24 influences susceptibility to PC in men of European ancestry. Although our study did not confirm the allelic association of rs1447295, meta-analysis of this SNP provided support to previous reported associations. Further, this study implicates the 8q24 region with aggressive forms of PC.

Individual and cumulative effect of prostate cancer risk‐associated variants on clinicopathologic variables in 5,895 prostate cancer patients

More than a dozen single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk from genome-wide association studies (GWAS). Their association with PCa aggressiveness and clinicopathologic variables is inconclusive. Twenty PCa risk SNPs implicated in GWAS and fine mapping studies were evaluated in 5,895 PCa cases treated by radical prostatectomy at Johns Hopkins Hospital, where each tumor was uniformly graded and staged using the same protocol. For 18 of the 20 SNPs examined, no statistically significant differences (P > 0.05) were observed in risk allele frequencies between patients with more aggressive (Gleason scores > or =4 + 3, or stage > or =T3b, or N+) or less aggressive disease (Gleason scores < or =3 + 4, and stage < or =T2, and N0). For the two SNPs that had significant differences between more and less aggressive disease rs2735839 in KLK3 (P = 8.4 x 10(-7)) and rs10993994 in MSMB (P = 0.046), the alleles that are associated with increased risk for PCa were more frequent in patients with less aggressive disease. Since these SNPs are known to be associated with PSA levels in men without PCa diagnoses, these latter associations may reflect the enrichment of low grade, low stage cases diagnosed by contemporary disease screening with PSA. The vast majority of PCa risk-associated SNPs are not associated with aggressiveness and clinicopathologic variables of PCa. Correspondingly, they have minimal utility in predicting the risk for developing more or less aggressive forms of PCa.

Critical Appraisal of Prostate-specific Antigen in Prostate Cancer Screening: 20 Years Later

Prostate-specific antigen (PSA) is secreted by all types of prostate epithelial cells and has been used for 2 decades as a biologic marker for prostate cancer (PCa). Since the implementation of PSA screening in the United States, the detection of PCa has increased, accompanied by a decrease in the incidence of high-grade cancer and PCa-specific mortality rates. It has been suggested that these decreases have resulted from the enhanced detection of PCa while still curable. These data have been the impetus for early detection programs, which have recommended the initiation of screening as early as 40 years of age. Despite widespread use, PSA screening remains controversial, principally because of the lack of evidence from randomized controlled trials demonstrating a mortality benefit that could outweigh the concerns of the costs of overdiagnosis and overtreatment. Two ongoing, randomized controlled trials are examining whether screening reduces the risk of PCa-related mortality, and the results of these studies are expected soon. Although it has its limitations, PSA still remains the best-studied marker for the detection of PCa.

Endothelial NOS, estrogen receptor β, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer

The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor beta (ERbeta). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERbeta/eNOS, ERbeta/HIF-1alpha, or ERbeta/HIF-2alpha combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERbeta and nuclear eNOS plus HIF-2alpha being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERbeta, and HIF-2alpha expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases.

Research augurs new prostate cancer test

Nurses may soon have a simple test to detect aggressive forms of prostate cancer, which could reduce the number of patients at minor risk undergoing painful interventions such as biopsies and radiotherapy.

Expression of androgen and estrogen related proteins in normal weight and obese prostate cancer patients

Obesity is associated with an aggressive form of prostate cancer and with alterations in androgen and estrogen metabolism. We hypothesized that changes in components of the sex steroid receptor axis may contribute to the clinical aggressiveness of prostate cancer in obese patients. A database was assembled containing clinical and pathological variables from 539 patients treated with radical prostatectomy at a single urban hospital between 1994 and 2002. Tissue microarrays were constructed from representative patients and expression of androgen receptor (AR), PSA, estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), and aromatase was examined. Higher BMI correlated strongly with black race, the presence of extra-capsular extension, and higher pathologic stage. Expression of AR, PSA, ERbeta and aromatase in cancerous epithelial cells did not differ according to obesity status. However, decreased expression of ERalpha and aromatase was observed in the stromal compartment surrounding non-cancerous acini in obese patients. We confirm the previously reported associations between obesity and aggressive clinical and pathologic features in our single-institution, urban teaching hospital. In comparing obese versus non-obese patients, there was no difference in expression of androgen or estrogen related proteins in cancerous epithelial cells. However, there was a down-regulation of ERalpha and aromatase in the stroma of obese patients. Our data suggest obesity may cause stromal changes in the sex steroid production and signaling pathways which may affect prostate cancer growth via intracrine/paracrine mechanisms.

Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer: Ouyang X, Jessen WJ, Al-Ahmadie H, Serio AM, Lin Y, Shih WJ, Reuter VE, Scardino PT, Shen MM, Aronow BJ, Vickers AJ, Gerald WL, Abate-Shen C, Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ

To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors–the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.

Bicalutamide failure in prostate cancer treatment: Involvement of Multi Drug Resistance proteins

Prolonged bicalutamide treatment induced pathology regression although relapses with a more aggressive form of prostate cancer have been observed. This failure could be due to androgen receptor mutation. In the present work we hypothesized an alternative mechanism responsible for bicalutamide failure involving activity of ATP-binding cassette (ABC) pumps such as P-glycoprotein, Breast Cancer Receptor Protein (BCRP), and Multi Resistant Proteins (MRPs) that extrude the androgen antagonist from the cell membrane. As experimental models androgen-dependent (LnCap) and androgen-independent (PC-3) prostate cancer cell lines have been employed. Bicalutamide has been tested in the cell lines mentioned above in the absence and in the presence of MC18, our potent P-glycoprotein/BCRP/MRP1 inhibitor. The results displayed that bicalutamide antiproliferative effect at 72 h was ameliorated in LnCap cells (EC 50 from 51.9 ± 6.1 µM to 17.8 ± 2.6 µM in the absence and in the presence of MC18, respectively) and restored in PC-3 cells (EC 50 from 150 ± 2.4 µM to 60 ± 3.5 µM in the absence and in the presence of MC18, respectively). Moreover, we established the contribution of each transporter employing stable transfected cells (MDCK) overexpressing P-glycoprotein or BCRP or MRP1 pump. The results displayed that P-glycoprotein and BCRP were involved in bicalutamide efflux while MRP1 was unable to bind the antiandrogen drug.