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This study investigates oxidative stress and bioindicators of reproductive function in wild white sucker (Catostomus commersoni) collected from environments receiving pulp and paper mill effluent discharges in northern Ontario. Samples were collected over an eight-year period adjacent to three pulp and paper mills using a variety of processing and bleaching techniques. Fish collected downstream of pulp and paper mills within the Moose River basin exhibited elevated hepatic and gonadal 2-thiobarbituric acid reactive substances (TBARS), the presence of which is indicative of oxidative stress in these tissues. Within the Jackfish Bay system, exposure to pulp and paper mill effluent did not elevate hepatic or gonadal TBARS. Hepatic cytochrome P4501A activity (CYP1A) and fatty acyl-CoA oxidase (FAO) activities were frequently increased in livers of Moose River basin fish exposed to pulp and paper mill effluent, while lower activities of both enzymes were found within fish from the Jackfish Bay system. This suggests that oxidative stress may be related to CYP1A and FAO activities. Within the Moose River system, increases in measures of oxidative stress (TBARS, FAO) were generally coincident with decreased levels of 17 beta-estradiol; however, testosterone was often lower in Jackfish Bay system fish without any commensurate changes in oxidative stress. The suite of reproductive and oxidative stress parameters measured in this study varied between seasons and mills suggesting responses to effluent are dynamic and effects are complicated by different receiving environments. The relationship between gonad size, gonadal oxidative stress, and circulating plasma steroids remains unclear.

Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phase III studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to a significant increase in median overall survival.This position paper aims to provide current data and orientation in the evidence-based treatment of mPC patients in daily clinical practice.A German group of clinical experts analyzed the current data and developed criteria for the treatment of mPC patients in daily clinical practice.In the current treatment of hormone-naïve mPC, a beneficial effect of chemotherapy in addition to ADT has become evident. Provided patients are in an appropriate condition, those with a high metastatic load should receive chemotherapy in addition to ADT. Especially in high-risk mCRPC patients (PSA114 ng/ml, visceral metastasis, ADT response12 months, tumor-associated complaints), first-line chemotherapy is indicated. After docetaxel failure, continuous treatment with cabazitaxel shows superior overall survival compared to sustained antihormonal therapy.Chemotherapy is firmly established in treating patients with mCRPC. Long-term, it will be important to identify molecular predictors. The authors suggest the early use of chemotherapy in hormone-naïve mPC, but note that the approval in this indication is currently nonexistent. After disease progression, patients should be treated analogous to mCRPC.

More than a third of cancers are diagnosed in people over the age of 75. Androgen deprivation for prostate cancer and aromatase inhibitors in breast cancer accelerate age-related bone loss and increase fracture rates. BMD should be checked by dual energy X-ray absorptiometry at baseline and, dependent on risk, every 12–24 months. Sufficient calcium, vitamin D and exercise are part of primary fracture prevention. Resistance exercise in particular may improve functional activity and bone density. In men at increased fracture risk and women with postmenopausal early breast cancer, antiresorptive treatment is warranted to reduce fracture rate and to increase overall survival in breast cancer. Bone metastases (BM) are common in breast and prostate cancer and lytic bone lesions typical of multiple myeloma. They can cause fractures, pain and spinal cord compression, require surgery or radiation for symptom relief, and lead to hypercalcaemia. Multidisciplinary working with patients and carers can improve quality of life for elderly patients with BM and mitigate the adverse consequences of therapy. Bisphosphonates and other osteoclast inhibitors such as denosumab reduce this morbidity, improve quality of life and reduce pain. Especially in the elderly, attention should be paid to renal function and to risk factors for osteonecrosis with bone-modifying agents. Attention should also be paid to hypocalcaemia risk, which can be considerable in elderly men with metastatic prostate cancer and vitamin D deficiency. We urgently need further research specifically directed at assessing risks and benefits of bone targeted treatments in the growing population of elderly cancer patients.

A number of traditional Chinese medicines (TCMs) are widely used in prostate cancer treatment in China. The aim of this study was to test the efficacy of a TCM, Zhoushi Qiling Decoction (ZQD), in combination with androgen deprivation therapy (ADT) and explore its underlying mechanism. A total of 151 patients were recruited to receive ADT treatment or ADT+ZQD treatment. The survival of patients who received ADT+ZQD treatment was significantly higher than those who received ADT therapy only. DU145 prostate cancer cells were treated with ZQD (50 mg/mL) for 24 h in vitro and expression levels of an array of miRNAs were examined. Our results suggested that miR-143 demonstrated prominent upregulation in DU145 cells after treatment with ZQD. In patient serum samples, miR-143 expression was also significantly upregulated after ADT+ZQE treatment, which was however absent in patients treated with ADT only. In DU145 cells, ZQD treatment led to a dose-dependent increase in apoptosis, which could be reduced by anti-miR-143 treatment. There was a binding site between miR-143 and B cell CLL/lymphoma-2 (Bcl-2) and ZQD treatment reduced Bcl-2 expression. ZQD treatment led to increased caspase-3 and Bax expression. ZQD treatment could promote apoptosis of prostate cancer cells by promoting miR-143 upregulation, which could be a possible mechanism underlying the inhibitory effect of ZQD in prostate cancer in patient.

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

Purpose To investigate men’s experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. Methods A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. Results Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. Conclusions These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.

Although patients with early localized prostate cancer can survive longer, castration-resistant prostate cancer (CRPC) has gradually emerged with the use of androgen deprivation therapy (ADT). N-Myc and TEM8 play a vital role in the progression of several cancer types. However, the underlying mechanism of how N-Myc and TEM8 promote the progression of prostate cancer remains unclear. In this study, the expression of N-Myc and TEM8 was detected in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissues by immunohistochemistry (IHC). LNCaP cell lines were maintained in RPMI 1640 medium supplemented with 10% charcoal-stripped fetal bovine serum. Subsequently, R language software was used to verify our results. Tubule formation assay of human umbilical vein endothelial cell (HUVEC) was conducted to examine the effect of N-Myc and TEM8 overexpression on angiogenesis in prostate cancer cells. IHC results showed a positive correlation between the expression of N-Myc and TEM8 in prostate cancer tissues. Further analysis showed that N-Myc and TEM8 were associated with clinicopathological features and poor prognosis in prostate cancer patients. Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. Additionally, N-Myc and TEM8 overexpression was associated with therapeutic resistance. We further found that N-Myc promoted angiogenesis and therapeutic resistance in prostate cancer via TEM8. Hence, targeting N-Myc/TEM8 pathway in prostate cancer would be a novel therapeutic strategy to enhance the treatment of prostate cancer patients.

Background Prostate cancer (PC) is the most frequent neoplasia in the male population and androgen deprivation therapy (ADT) is frequently used in the management of the disease. Aim To evaluate the effect of ADT exposure on cognitive status, grey matter volume (GMV) and white matter lesion (WML) load. Methods Fifty ADT patients and fifteen PC-non-ADT (control) patients were included in the study. A neuropsychological evaluation was performed and a magnetic resonance imaging (MRI), with anatomical T1 and FLAIR sequences, was performed to evaluate the GMV and the WML burden. Results Most of the patients included in the study presented a significant cognitive impairment (CI). No significant differences were identified in the cognitive assessment between the studied groups, but when considering the educational background intragroup differences were found.No significant difference of GMV and WML volume were identified between groups, but a negative relationship between the ADT period and the GMV was identified. Furthermore, a significant positive association between the age and the lesion volume was found in the ADT group (β=.406; p=.004). Conclusion PC patients exposed to ADT present an acceleration of age-related brain changes, such as WML development and GMV loss.

Rationale: The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge. Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling. KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC. However, the mechanisms of KDM4B involvement in CRPC remain largely unknown. Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target. Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation (in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B. Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region. Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions. The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc. We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes (LDHA, ENO1, and PFK). Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner. We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome. Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression. Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR.

The aim of the present study was to explore the potential impact of upfront metastases-directed therapy (MDT) in terms of prolongation of castration-sensitive phase in a series of oligorecurrent castration-sensitive prostate cancer (PC) patients. The present article is a multicenter retrospective study. The population of interest was castrate-sensitive oligorecurrent PC, defined as the presence of 1–3 uptakes in non-visceral sites such as bones or nodes detected by means of 18F-Choline PET/CT or 68-Gallium PSMA PET/CT. Primary endpoint was the time to castration resistance. Secondary endpoints were ADT-free survival, local progression-free survival, and overall survival. Eighty-two patients and 118 lesions were analyzed. The median time to castration resistance for the entire population of the study was 49 months (95% CI 43.6–54.4 months). The 1- and 2-year TTCR-free survival rates were 94% and 82%, respectively. At the time of analysis, 52 patients were still in the castration-sensitive phase of the disease. In this cohort of patients, the median ADT-free survival was 20 months (range 3–69 months). On the other hand, during follow-up 30 patients switched to the castration-resistant phase of disease. In this last group of patients, the median ADT-free survival was 20 months (range 4–50 months). After the ADT administration, the median castration-sensitive phase was 29 months (range 5–71 months). Castration resistance generally occurs at a median follow-up of 24–36 months following ADT. In the current study, upfront MDT does not decrease the time from initiation of ADT to castration resistance.

Background Androgen deprivation therapy (ADT) increases the risk of metabolic adverse effects among patients with prostate cancer. The transformative impact of mobile health (mHealth) apps may benefit men managing activity and nutrition at home. Objective This study aimed to evaluate the usability and patient experience of a newly developed mHealth app among prostate cancer patients on ADT and physicians’ beliefs about the potential benefits of using this app. Methods This study took place over 2 months, beginning in March 2019. A sample of 5 patients (age 45-75 years) initiating ADT participated in a semistructured focus group discussion with a facilitator. The study participants also included 5 specialist physicians who provided in-depth interviews. An institutional review board–approved script was used to guide both the focus group and physician interviews. Usability was tested through specific scenarios presented to the patients, including downloading the mHealth app, entering information on physical activity and meals, and navigating the app. The focus group and interviews were audio recorded and transcribed. Content analysis was used to analyze the transcripts iteratively and exhaustively. Thematic discrepancies between reviewers were resolved through consensus. Results The mean age of the patients was 62 years. This group included 4 White and 1 Latin American patients. The physician specialists included 2 urologists, 2 medical oncologists, and 1 radiation oncologist. Analyses revealed that the patients appreciated the holistic care enabled by the app. Difficulties were observed with registration of the app among 60% (3/5) of the patients; however, all the patients were able to input information about their physical activity and navigate the options within the app. Most patients (4/5, 80%) were able to input data on their recent meal. Among the health care physicians, the dominant themes reflected in the interviews included undermining of patients ability to use technology, patients’ fear of technology, and concern for the ability of older patients to access technology. Conclusions The patients reported an overall positive experience of using an mHealth app to record and track diet and exercise. Usability was observed to be an important factor for adoption and was determined by ease of registration and use, intuitive appearance of the app, and focus on holistic cancer care. The physicians believed that the app was easy to use but raised concerns about usability among older men who may not typically use smartphone apps.

Objectives: Transgender individuals submitted to hormone or surgical treatment may have alterations in their bone metabolism as these elements are important players in bone remodeling. We aimed to study bone mineral density (BMD) and body composition in transwomen undergoing cross-sex hormonal treatment (CSHT) from Brazil for over 3 years, comparing them with female and male controls. Methods: 93 individuals (31 transwomen, 31 females and 31 males paired for age and body mass index) were studied for bone mass, and body composition by densitometry (by DXA). Epidemiological and clinical data were collected through direct questioning. Results: Low bone mass (T score ≤2) was found in 12.9% of transwomen; in 3.2% of females and 3.3% of males. Transwomen individuals had lower spine Z score (0.26 ± 1.42 vs 0.50 ± 1.19) and femur Z score (−0.41 ± 0.95 vs 0.29 ± 1.04) than females. They had lower total femur Z score than males (−0.41 ± 0.95 vs 0.20 ± 0.83). Lean mass values correlated positively with total femur BMD (ρ = 0.40; 95% confidence interval = 0.009–0.68; p = 0.04) and BMD in femoral neck (ρ = 0.48; 95% confidence interval = 0.11–0.74; p = 0.01) but neither the type of therapy received nor the time that they were used, impacted bone mass. Conclusion: Low BMD is found frequently in transwomen and it is correlated with lean body mass. Advances in knowledge: There are few studies of the effects of hormone therapy on the bones and muscles of transwomen. This study demonstrated that significant changes occur, and that the population studied needs greater care in musculoskeletal health.

Prostate-specific membrane antigen (PSMA) targeted PET has a high detection rate for biochemical recurrence (BCR) of prostate cancer (PCa). Nevertheless, even at high prostate-specific antigen (PSA) levels (> 3 ng/ml), a relevant number of PSMA-PET scans are negative, mainly due to PSMA-negative PCa. Our objective was to investigate whether PSMA-expression patterns of the primary tumour on immunohistochemistry (IHC) are associated with PSMA-PET detection rate of recurrent PCa. Methods: Retrospective institutional review board approved single-centre analysis of patients who had undergone 68Ga-PSMA-11-PET for BCR after radical prostatectomy (RPE) between 04/2016 and 07/2019, with tumour specimens available for PSMA-IHC. Clinical information (age, PSA-level, ongoing androgen deprivation therapy (ADT), Gleason score) and PSMA-IHC of the primary tumour were collected and their relationship to results from PSMA-PET (positive/negative) was investigated using a multiple logistic regression analysis. Results: 120 PSMA-PET scans in 74 patients were available for this analysis. Overall detection rate was 62% (74/120 scans), with a mean PSA value at scan time of 0.99 ng/ml (IQR 0.32-4.27). Of the clinical factors, only PSA-level and ADT were associated with PSMA-PET positivity. The percentage of PSMA-negative tumour area on IHC (PSMA%neg) had a significant association to PSMA-PET negativity (OR = 2.88, p < 0.001), while membranous PSMA-expression showed no association (p = 0.73). The positive predictive value of PSMA%neg ≥ 50% for a negative PSMA-PET was 85% (13/11) and for a PSMA%neg of 80% or more, 100% (9/9). Conclusions: PSMA-negative tumour area on IHC exhibited the strongest association with negative PSMA-PET scans, beside PSA-level and ADT. Even at very high PSA levels, PSMA-PET scans were negative in most of the patients with PSMA%neg ≥ 50%.

Long non-coding RNAs (lncRNAs) have been found essential for tumorigenesis of prostate cancer (PC), but its role in the regulation of castration-resistant prostate cancer (CRPC) is poorly identified. Here, we showed that a lncRNA, Breast-Cancer Anti-Estrogen Resistance 4 (BCAR4), which plays a pivotal role in the tamoxifen-resistance of breast cancer, was significantly upregulated in CRPC, but not in castration-sensitive prostate cancer (CSPC), compared to normal prostate tissue. High BCAR4 levels in CRPC were correlated with poor patients’ overall survival. Androgen increased growth and migration of androgen receptor (AR)-positive PC346 cells, which was abolished by the antagonist of androgen. Overexpression of BCAR4 in PC346 cells increased cell growth and migration, but turned the cells insensitive to androgen. On the other hand, growth and migration of AR-negative DU145 cells are insensitive to androgen, while depletion of BCAR4 in DU145 cells not only decreased cell growth, but also turned the cells sensitive again to androgen. Moreover, BCAR4 activated GLI2 downstream genes, and correlated with the levels of these GLI2-target genes in CRPC. Depletion of GLI2 abolished the effects of BCAR4 on cell growth and migration. Together, our data suggest that BCAR4 may activate GLI2 signaling in PC to contribute to castration resistance.

In clinical practice, few prostate cancer (PCa) patients are associated with metabolic syndrome (MetS), while few others acquire MetS during treatment. Whether the treatment of PCa increases the occurrence of MetS remains to be confirmed. This study reviewed the changes in MetS patients before and after PCa treatment to evaluate the effects of various treatment methods on MetS. We analyzed data of 1162 PCa patients, whether or not diagnosed with MetS, and changes in MetS patients after PCa treatment. Data of lower urinary tract symptoms, C-reactive protein (CRP), platelet distribution width (PDW), prostate-specific antigen (PSA), Gleason score, clinical stage, treatment methods, and progressive incidents were evaluated using logistic regression according to MetS diagnosis. The results showed significant differences in the prevalence of MetS before (17.38%) and after (23.67%) PCa treatment (P

Objective: It has been established that survival and toxicity outcomes in some cancer types could be influenced by haemoglobin (Hb) levels. This study aims to determine if pre-treatment Hb is associated with late toxicity or survival outcomes in prostate cancer. Methods: Data from one Phase III randomised controlled trial and one single arm translational trial were analysed. Patients had localized prostate cancer and received ≥70 Gy radiotherapy and neo-adjuvant androgen deprivation between 1997 and 2013. Results: 302 males were included. Median follow-up was 6.8 years for toxicity and 10.3 years for survival outcomes. Patients with Hb below the reference range were more likely to experience Grade 2–3 late gastrointestinal toxicity than patients with Hb within the range (p = 0.050). Neither late genitourinary toxicity, erectile function toxicity, prostate-specific antigen relapse free survival nor overall survival of patients were statistically significantly different between groups. Conclusion: Anaemia in prostate cancer is found in the minority of patients and is usually mild. Prostate cancer patients undergoing radiotherapy with low Hb were more likely to experience Grade 2–3 late gastrointestinal toxicity. Advances in knowledge: This study is one of the first in the published literature to investigate the role of Hb in prostate cancer toxicity and survival. We have found an association between Hb below the reference range and late GI toxicity. Consideration should be given to further investigating patients with iron deficiency anaemia to guide management options and outrule underlying GI pathology before proceeding with radiotherapy treatment.

OBJECTIVE: Hot flushes and night sweats (HFNS) are experienced by up to 80% of prostate cancer patients undergoing androgen deprivation therapy (ADT). This study evaluates the effects of a guided self-help cognitive behavioural therapy (CBT) intervention on HFNS problem-rating (primary outcome), HFNS frequency, mood and health-related quality of life (secondary outcomes) in patients undergoing ADT.METHODS: Patients reporting treatment-induced HFNS were randomly assigned to CBT (n = 33) or treatment as usual (TAU) (n = 35), stratified for cancer type. The CBT intervention included a booklet, CD plus telephone contact during a 4-week period. Validated self-report questionnaires were completed at baseline, 6 weeks and 32 weeks after randomisation. The primary outcome was HFNS problem rating (perceived burden of HFNS) at 6 weeks after randomisation. Potential moderators and mediators were examined. Data analysis was conducted on a modified intention-to-treat basis.RESULTS: Compared with TAU, CBT significantly reduced HFNS problem rating (adjusted mean difference: -1.33, 95% CI -2.07 to -0.58; p = 0.001) and HFNS frequency (-12.12, 95% CI -22.39 to -1.84; p = 0.02) at 6 weeks. Improvements were maintained at 32 weeks, but group differences did not reach significance. There were significant reductions in negative HFNS Beliefs and Behaviours following CBT, but not in mood or quality of life.CONCLUSIONS: Guided self-help CBT appears to be a safe and effective brief treatment for men who have problematic HFNS following prostate cancer treatments. Further research might test the efficacy of the intervention in a multicentre trial. © 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.

// Anne Offermann 1, * , Ignacija Vlasic 1, * , Isabella Syring 2, 6, 7 , Wenzel Vogel 1 , Christian Ruiz 3 , Tobias Zellweger 4 , Cyrill A. Rentsch 5 , Susanne Hagedorn 1 , Jochen Behrends 8 , Michael Nowak 6, 7 , Axel Merseburger 9 , Lukas Bubendorf 3 , Jutta Kirfel 7 , Stefan Duensing 10 , Zaki Shaikhibrahim 1, * , Sven Perner 1, * 1 Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany 2 Department of Urology, University Hospital Bonn, Bonn, Germany 3 Institute for Pathology, University Hospital Basel, Basel, Switzerland 4 Department of Urology, St. Claraspital, Basel, Switzerland 5 Department of Urology, University Hospital Basel, Basel, Switzerland 6 Section of Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany 7 Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany 8 Core Facility Fluorescence Cytometry, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany 9 Department of Urology, University Hospital Luebeck, Luebeck, Germany 10 Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany * These authors have contributed equally to this work Correspondence to: Sven Perner, email: sven.perner@uksh.de Keywords: mediator complex, MED15, castration-resistant prostate cancer, androgen deprivation, PI3 kinase Received: April 15, 2016 Accepted: November 21, 2016 Published: December 10, 2016 ABSTRACT Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFs activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFs-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.

// Indranil Chattopadhyay 1 , Jianmin Wang 2 , Maochun Qin 2 , Lingqiu Gao 3 , Renae Holtz 3 , Robert L. Vessella 4 , Robert W. Leach 5 , Irwin H. Gelman 3 1 Department of Life Sciences, School of Basic and Applied Science, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India 2 Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Department of Urology, University of Washington, Seattle, WA, USA 5 Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA Correspondence to: Irwin H. Gelman, email: Irwin.gelman@roswellpark.org Keywords: Src, androgen receptor, castration-recurrent prostate cancer, transcriptome, cistrome Received: April 03, 2016 Accepted: December 05, 2016 Published: December 31, 2016 ABSTRACT Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset ( DPP4 , BCAT1 , CNTNAP4 , CDH3 ) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.

// Jingbo Qiao 1, 2 , Magdalena M. Grabowska 1, 3 , Ingrid S. Forestier-Roman 4 , Janni Mirosevich 1, 3 , Thomas C. Case 1, 3 , Dai H. Chung 1, 2 , Justin M.M. Cates 5 , Robert J. Matusik 1, 3 , H. Charles Manning 6 , Renjie Jin 1, 3 1 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA 2 Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA 3 Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA 4 Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 5 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA 6 Institute of Imaging Science and Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, USA Correspondence to: Renjie Jin, email: renjie.jin@vanderbilt.edu Keywords: GRP/GRP-R, NF-kappa B, androgen receptor variants, prostate cancer, progression Received: April 04, 2016 Accepted: July 27, 2016 Published: August 17, 2016 ABSTRACT Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone — gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.

Progression of castration-resistant tumors is frequent in prostate cancer. Current systemic treatments for castration-resistant prostate cancer only produce modest increases in survival time and self-renewing Tumor-Initiating Cells (TICs) are suspected to play an important role in resistance to these treatments. However it remains unclear whether the same TICs display both chemo-resistance and self-renewing abilities throughout progression from early stage lesions to late, castration resistant tumors. Here, we found that treatment of mice bearing LNCaP-derived xenograft tumors with cytotoxic (docetaxel) and anti-androgen (flutamide) compounds enriched for cells that express TROP2, a putative TIC marker. Consistent with a tumor-initiating role, TROP2high cells from androgen-sensitive prostate cancer cell lines displayed an enhanced ability to re-grow in culture following treatment with taxane-based chemotherapy with or without androgen blockade. TROP2 down-regulation in these cells reduced their ability to recur after treatment with docetaxel, in the presence or absence of flutamide. Accordingly, in silico analysis of published clinical data revealed that prostate cancer patients with poor prognosis exhibit significantly elevated TROP2 expression level compared to low-risk patients, particularly in the case of patients diagnosed with early stage tumors. In contrast, in androgen-independent prostate cancer cell lines, TROP2high cells did not exhibit a differential treatment response but were characterized by their high self-renewal ability. Based on these findings we propose that high TROP2 expression identifies distinct cell sub-populations in androgen-sensitive and androgen-independent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.

The main challenge in the treatment of prostate cancer (PCa) is that the majority of patients inevitably develop resistance to androgen deprivation. However, the mechanisms involved in hormone independent behavior of PCa remain unclear. In the present study, we identified androgen-induced miR-135a as a direct target of AR. Functional studies revealed that overexpression of miR-135a could significantly decrease cell proliferation and migration, and induce cell cycle arrest and apoptosis in PCa. We identified RBAK and MMP11 as direct targets of miR-135a in PCa by integrating bioinformatics analysis and experimental assays. Mechanistically, miR-135a repressed PCa migration through downregulating MMP11 and induced PCa cell cycle arrest and apoptosis by suppressing RBAK. Consistently, inverse correlations were also observed between the expression of miR-135a and RBAK or MMP11 in PCa samples. In addition, low miR-135a and high RBAK and MMP11 expression were positively correlated with PCa progression. Also, PI3K/AKT pathway was confirmed to be an upstream regulation signaling of miR-135a in androgen-independent cell lines. Accordingly, we reported a resistance mechanism to androgen deprivation therapy (ADT) mediated by miR-135a which might be downregulated by androgen depletion and/or PI3K/AKT hyperactivation, in castration-resistant prostate cancer (CRPC), thus promoting tumor progression. Taken together, miR-135a may represent a new diagnostic and therapeutic biomarker for castration-resistant PCa.

Genetic profiling of urine cell free DNA (cfDNA) has not been evaluated in advanced prostate cancer. We performed whole genome sequencing of urine cfDNAs to identify tumor-associated copy number variations in urine before and after initiating androgen deprivation therapy in HSPC stage and docetaxel chemotherapy in CRPC stage. A log2 ratio-based copy number analysis detected common genomic abnormalities in prostate cancer including AR amplification in 5/10 CRPC patients. Other abnormalities identified included TMPRSS2-ERG fusion, PTEN gene deletion, NOTCH1 locus amplification along with genomic amplifications at 8q24.3, 9q34.3, 11p15.5 and 14q11.2, and deletions at 4q35.2, 5q31.3, 7q36.3, 12q24.33, and 16p11.2. By comparing copy number between pre- and post-treatment, we found significant copy number changes in 34 genomic loci. To estimate the somatic tumor DNA fraction in urine cfDNAs, we developed a Urine Genomic Abnormality (UGA) score algorithm that summed the top ten most significant segments with copy number changes. The UGA scores correlated with tumor burden and the change in UGA score after stage-specific therapies reflected disease progression status and overall survival. The study demonstrates the potential clinical utility of urine cfDNAs in predicting treatment response and monitoring disease progression.

Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients.