Development Of Aggressive Prostate Cancer Research Articles

Abstract 6285: Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient prostate cancer

Abstract Mutation or loss of the tumor suppressor genes BRCA1 and BRCA2 promotes the development of aggressive prostate cancer with poor outcomes and a high risk of metastatic relapse. Approximately 15% of metastatic prostate tumors are BRCA1/2-deficient. These tumors are frequently resistant to standard-of-care treatments that block androgen receptor (AR) function, although the mechanisms underlying this effect remain unclear. PARP inhibitors are synthetically lethal with BRCA1/2-deficiency and are commonly used as a late-line treatment in metastatic prostate cancer; however, both preclinical and clinical data have provided conflicting results on whether PARP inhibitors can be effective in BRCA1/2-proficient prostate tumors. BRCA1, BRCA2, PARP-1, and PARP-2 all have proposed roles in regulating transcription and the chromatin landscape. We therefore hypothesized that loss of BRCA1, BRCA2, and/or inhibition of PARP modulates AR function through changes in global chromatin structure and transcriptional pathways. We used patient-derived xenograft models and next-generation sequencing techniques to profile AR function in BRCA1/2-deficient vs. proficient prostate tumors. We found that loss of BRCA1 and BRCA2 is associated with chromatin accessibility changes, and differentially accessible regions correlate with DNA binding motifs for AR and AR cofactors. ChIP-seq for AR in these tumors demonstrated that BRCA1/2-deficiency is associated with an altered AR cistrome and a global decrease in AR genomic binding. Corresponding RNA-seq data confirmed a downregulated androgen response in BRCA1/2-deficient tumors. In cell line models, inhibition of PARP1 and PARP1/2 inhibited AR-driven transcription. Combining PARP inhibition with either androgen deprivation or the AR antagonist enzalutamide dampened the growth-inhibitory effects of PARP inhibitor treatment. Together, these results indicate that BRCA1/2-deficiency and PARP inhibition modulate AR function in prostate cancer. Citation Format: Nicole A. Traphagen, Esme Wheeler, Rong Li, Xintao Qiu, Myles Brown. Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6285.

Clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer.

e17049 Background: Although prostate cancer (PC) is heterogeneous, the rate of patients diagnosed with aggressive metastatic disease at a young age has been increasing. Prior studies defining genetic abnormalities in high-risk PC have not focused on this unique population of patients, thus the clinical and molecular features of these lethal PC phenotypes are not well described. Methods: This multi-institutional study evaluated two cohorts. Cohort 1, reported here, included early-onset (age ≤ 60) PC that was metastatic (N+ or M+) at diagnosis or PC that metastasized within 5 years post curative intent/local therapy. Cohort 2 included men with metastatic hormone sensitive PC who rapidly progressed (≤ 14 months) after systemic therapy. Data was collected to define clinical and genomic profiles, including sequencing of somatic & germline DNA, circulating tumor DNA and tumor RNA. Standard descriptive statistics were used. Results: 44 patients were enrolled. Median age at diagnosis was 55 years (range 41-60); 84% were White and 14% were Black. Median prostate specific antigen at diagnosis was 20 (range 1-534 ng/mL). 54% reported a family history of PC, while breast and colorectal cancer were reported in 35% and 14%, respectively. 4.5% reported a history of biochemical agent exposure. 58.5% of patients had De Novo distant metastatic disease (56% of these were low-volume) and 59.5% had a Gleason score of 9-10. 59% had received prior local therapy. Germline and somatic genetic data are available for 36 patients (4 are pending). The most common somatic mutation was in TP53 (n=15), followed by BRAF (n=14), AR (n=7), ERBB3 & MYC (n=5 each), CDKN2B, HRAS, MUC4, OBSCN & SPOP (n=4 each). Additional unique mutations in over 1,000 genes were also identified. Germline mutations were detected in BRCA2, ATM, ATP7B & FBN1 (n=3 each), RB1, CDH1, MYBPC3, MYH11 & MYH7 (n=2 each). 11 other unique germline mutations were also identified. Germline mutations were identified in genes previously implicated in hereditary PC ( BRCA2, ATM, PALB2, BRIP1 & CHEK2), with an overall germline incidence of 25%. There were also incidental germline mutations in genes related to hereditary cardiac conditions ( MYBPC, MYH11, MYH7), as well as other hereditary cancers ( RB1 and CDH1). Conclusions: This study evaluated specific criteria to define risk factors associated with the development of aggressive PC at a young age. Nearly 90% of these patients had a family history of cancer, with over 50% reporting a family history of PC. Somatic mutations were identified in genes such as TP53 that are frequently associated with aggressive disease. Additionally, there was enrichment for germline mutations associated with PC that exceeded what has previously been reported and enrichment of mutations not commonly included in PC genetic risk panels. Thus, more work is needed to define characteristics of this high-risk population and optimize management.

DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men.

BackgroundAltered DNA damage response (DDR) has emerged as an important mechanism for the development of aggressive prostate cancer among men of European ancestry but not other ancestry groups. Because common mechanisms for aggressive disease are expected, we explored a large panel of DDR genes and pathways to demonstrate that DDR alterations contribute to development of aggressive prostate cancer in both African American and European American men.MethodsWe performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher’s exact tests. Secondary analysis examined if carrier frequencies differed by ancestry.ResultsLethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10−4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02).ConclusionsOur findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.

Implication of β2-adrenergic receptor and miR-196a correlation in neurite outgrowth of LNCaP prostate cancer cells.

The β2-adrenergic receptor has been shown to be involved in neuroendocrine differentiation and to contribute to the development of aggressive prostate cancer. In this study we have investigated whether miR-196a plays a role in the regulation of the β2-adrenergic receptor in the LNCaP prostate cancer cell line. Our results show that the expression of miR-196a is elevated in LNCaP prostate cancer cells with reduced levels of β2-adrenergic receptor after stably transfection with three different shRNAs. Furthermore, treatment with β-blockers showed that this upregulation is strictly related to the low levels of β2-adrenergic receptor and not to the inhibition of the receptor signaling activity. Finally, we found that the reduced ability of LNCaP cells with low levels of β2-adrenergic receptor to initiate neuroendocrine differentiation under androgen depletion conditions is mediated by miR-196a. In conclusion, this study provides the rational for a role of miR-196a in the β2-adrenergic receptor mediated neuroendocrine differentiation of LNCaP prostate cancer cells.

IL-4 Counteracts the Cytotoxic Effects of Peripheral Blood Mononuclear Cells on Hormone-sensitive Prostate Cancer Cells.

Proinflammatory cytokines play an essential role in the development and progression of prostate cancer (PCa). Especially interleukine (IL-)6 is involved in the development of aggressive PCa. Peripheral blood mononuclear cells (PBMC) have been reported to interact with cancer cells and subsequently lead to increased production of pro-inflammatory cytokines. However, the role of anti-nflammatory cytokines, such as IL-4 is still largely unexplored in prostate cancer. In the present study, we investigated the effects of IL-4 on PBMC co-cultured with PCa cells. PBMC were co-culured with the PCa cell lines LNCaP and LNCaP-IL6+. To avoid cell-cell contact, cancer and immune cells were separated using cell culture inserts with a 0.4 μm pore size membrane. Cell growth was assessed using the [3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium bromide] (MTT) assay. Cytokine levels were measured using a BD™Cytometric Bead Array. Cell viability of LNCaP cells decreased massively when cells were co-cultured with PBMC. Pre-incubation with IL-4 could partly rescue the observed effect of cell viability of LNCaP cells co-cultured with PBMC. In contrast, cell viability of the LNCaP-IL6+ cell line was not affected when co-cultured with PBMC. IL-4 counteracts the cytotoxic effects of PBMC on hormone-sensitive LNCaP cells and is involved in the immune escape and development of aggressive phenotypes of PCa.

Abstract PR09: MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry

Abstract Men of African ancestry (moAA) have increased likelihood for development of aggressive prostate cancer (PCa). PCa deaths are often associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy (ADT). The 8q24 chromosomal locus is a highly susceptible PCa region that carries risk genetic variants associated with increased incidence of aggressive PCa in moAA. This region also carries frequent amplifications of the PVT1 gene, a nonprotein coding gene that encodes microRNA-1205 whose function was previously unknown. We examined miR-1205 mRNA expression in a cohort of normal (n=22), benign prostatic hyperplasia (n=42), and PCa (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA in Ibadan, Nigeria. A Tukey post hoc test revealed decreased miR-1205 expression in benign prostatic hyperplasia (4.61 ± 7.5) and PCa (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5), suggesting that miR-1205 may function as a tumor suppressor and loss of miR-1205 is characteristic of PCa in moAA. In vitro studies revealed decreased miR-1205 expression in CRPC (C4-2B and 22RV1) cells when compared to non-CRPC (LNCaP) cells, suggesting a role for miR-1205 in CRPC. Furthermore, we observed significant inhibition of tumor growth in NOD/SCID gamma mice implanted with C4-2B cells that were administered our novel synthetic analog of miR-1205 (patent pending) when compared to mice treated with a scramble oligonucleotide, indicating that miR-1205 can suppress CRPC tumors. We identified Fry-like (FRYL) as a putative target of miR-1205 using a miSVR computer algorithm and subsequently observed FRYL and AR overexpression in prostate tumors compared to normal tissue from fourteen PCa patients when whole-transcriptome analysis was performed using the Galaxy web platform. Moreover, FRYL was overexpressed in CRPC cells when compared with non-CRPC cells, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 3′ UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 3′ UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor by directly targeting FRYL mRNA in PCa cells. FRYL is predicted to regulate dendritic branching, leading to our hypothesis that FRYL plays a role in the development of PCa with neuroendocrine differentiation (PCND), a resulting mechanism due to ADT resistance. We observed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of inducing PCND in LNCaP cells, suggesting that miR-1205 regulation of FRYL mRNA may play a role in PCND development. Further understanding miR-1205 regulation of FRYL may provide novel insights into the molecular mechanisms of aggressive PCa. This abstract is also being presented as Poster B068. Citation Format: Michelle K. Naidoo, Fayola Levine, Tamara Gillot, Thahmina Ali, Konstantinos Krampis, Akintunde Orunmuyi, E.O. Olapade-Olaopa, Olorunseun O. Ogunwobi. MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR09.

Abstract IA21: Social factors and prostate cancer disparities in African American men

Abstract African-American (AA) men experience the highest prostate cancer (PCa) incidence and mortality rates of all U.S. racial/ethnic groups. They are also known to present with more aggressive high-risk disease, especially of higher Gleason score and PSA levels. Factors contributing to the high burden of PCa among AA men are not known. AAs are exposed to considerably higher levels of social stressors such as institutional and interpersonal discrimination, early life adversity, crime, low socioeconomic status, social isolation, and resource-poor environments. These social stressors exist at multiple levels, from individual to neighborhood to institutional, and across the lifecourse, leading to chronic stress. These social stressors experienced among AA men may thus be a contributor to the development of aggressive PCa and high mortality. This presentation will explore the conceptual multilevel frameworks that emphasize the consideration and evaluation of exposures from “cells to society” to understand how “stress gets under the skin” to cause biologic vulnerability, specifically the high burden of PCa among AA men. Within the infrastructure of the new RESPOND (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Social Stress) Study, a nationwide cohort of 10,000 AA men with incident PCa, our project aims to: 1) Examine the associations between exposures to neighborhood social stressors and risk of aggressive PCa and mortality among AA and non-Hispanic White (NHW) men. Among population-based samples of all AA (N=149,000) and NHW (N=668,000) men diagnosed with PCa in the RESPOND catchment areas, we will link geospatial neighborhood data on segregation, racial composition, socioeconomic deprivation, and other social and built environment attributes to cancer registry data and examine the associations between these neighborhood factors and aggressive PCa and risk of mortality. 2) Examine the associations between exposures to multilevel social stressors across the lifecourse and risk of aggressive PCa among 10,000 AA men in RESPOND. 3) Examine the associations between exposures to multilevel social stressors across the lifecourse and genetic factors, as well as their combined effects in association with aggressive PCa. Covering 6 states and 1 metropolitan region and representing 38% of all AA men with PCa in the US, RESPOND will represent the single largest coordinated research effort to study aggressive PCa in AA men, with an innovative focus on social stressor exposures that are most relevant to this population. This project has the potential of identifying modifiable risk factors for aggressive prostate cancer to inform targeted prevention on a broad public health scale, such as targeting community support resources to neighborhoods with high stressors; the lifecourse approach will also provide the opportunity to identify critical time windows of disease susceptibility. The short-term impact of this research will be our expanded understanding of contextual- and individual-level stressors that are associated with aggressive disease among African American men, and the long-term impact, with future follow-up, is the determination of the effect of these social factors on disease progression and mortality. Citation Format: Scarlett Lin Gomez, Iona Cheng, Salma Shariff-Marco, Mindy C. DeRouen, Ann S. Hamilton, Daphne Y. Lichtensztajn, Pushkar Inamdar, Debby Oh, Laura Allen, Kirsten Beyer, Yuhong Zhou, Joseph Gibbons, Richard Pinder, David J. Press, David Conti, Christopher Haiman. Social factors and prostate cancer disparities in African American men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA21.

IFNL4-\u0394G is associated with prostate cancer among men at increased risk of sexually transmitted infections

Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide variant, rs368234815-TT/ΔG, in the IFNL4 gene encoding interferon λ4. Since the IFNL4-ΔG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an IFNL4-ΔG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of IFNL4-ΔG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking IFNL4-ΔG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and IFNL4-ΔG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene–environment interaction between IFNL4-ΔG and sexual activity may increase the risk of prostate cancer.

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer

Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

Baseline Prostate-specific Antigen Level in Midlife and Aggressive Prostate Cancer in Black Men

BackgroundProstate-specific antigen (PSA) measurement in midlife predicts long-term prostate cancer (PCa) mortality among white men. ObjectiveTo determine whether baseline PSA level during midlife predicts risk of aggressive PCa in black men. Design, setting, and participantsNested case-control study among black men in the Southern Community Cohort Study recruited between 2002 and 2009. A prospective cohort in the southeastern USA with recruitment from community health centers. A total of 197 incident PCa patients aged 40–64 yr at study entry and 569 controls matched on age, date of blood draw, and site of enrollment. Total PSA was measured in blood collected and stored at enrollment. Outcome measurements and statistical analysisTotal and aggressive PCa (91 aggressive: Gleason ≥7, American Joint Committee on Cancer stage III/IV, or PCa-specific death). Exact conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) for PCa by category of baseline PSA. Results and limitationsMedian PSA among controls was 0.72, 0.80, 0.94, and 1.03ng/ml for age groups 40–49, 50–54, 55–59, and 60–64 yr, respectively; 90th percentile levels were 1.68, 1.85, 2.73, and 3.33ng/ml. Furthermore, 95% of total and 97% of aggressive cases had baseline PSA above the age-specific median. Median follow-up was 9 yr. The OR for total PCa comparing PSA >90th percentile versus ≤median was 83.6 (95% CI, 21.2–539) for 40–54 yr and 71.7 (95% CI, 23.3–288) for 55–64 yr. For aggressive cancer, ORs were 174 (95% CI, 32.3–infinity) for 40–54 yr and 51.8 (95% CI, 11.0–519) for 55–64 yr. A composite endpoint of aggressive PCa based on stage, grade, and mortality was used and is a limitation. ConclusionsPSA levels in midlife strongly predicted total and aggressive PCa among black men. PSA levels among controls were similar to those among white controls in prior studies. Patient summaryProstate-specific antigen (PSA) level during midlife strongly predicted future development of aggressive prostate cancer among black men. Targeted screening based on a midlife PSA might identify men at high risk while minimizing screening in those men at low risk.

Beta-adrenergic signaling on neuroendocrine differentiation, angiogenesis, and metastasis in prostate cancer progression.

Prostate cancer is a complex, heterogeneous disease that mainly affects the older male population with a high-mortality rate. The mechanisms underlying prostate cancer progression are still incompletely understood. Beta-adrenergic signaling has been shown to regulate multiple cellular processes as a mediator of chronic stress. Recently, beta-adrenergic signaling has been reported to affect the development of aggressive prostate cancer by regulating neuroendocrine differentiation, angiogenesis, and metastasis. Here, we briefly summarize and discuss recent advances in these areas and their implications in prostate cancer therapeutics. We aim to provide a better understanding of the contribution of beta-adrenergic signaling to the progression of aggressive prostate cancer.

Overexpression of \u03b1 (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells

Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer.

Early-onset baldness and the risk of aggressive prostate cancer: findings from a case-control study.

We aimed to evaluate the associations between androgenetic alopecia at a young age and subsequent development of aggressive prostate cancer (PC). Using a case-control design with self-administered questionnaire, we evaluated the association between aggressive PC and very early-onset balding at age 20, and early-onset balding at age 40years in 1,941 men. Cases were men with high-grade and/or advanced stage cancer and controls were clinic based men who had undergone biopsy and were found to be histologically cancer negative. Additionally, for cases we assessed whether early-onset balding was associated with earlier onset of disease. Men with very early-onset balding at age 20years were at increased risk for subsequent aggressive PC [odds ratio (OR) 1.51, 95% confidence interval (CI) 1.07-2.12] after adjustment for age at baseline, family history of PC, smoking status, alcohol intake, body shape, timing of growth spurt and ejaculatory frequency. Additionally, these men were diagnosed with PC approximately 16months earlier than cases without the exposure. The effect was present particularly for men with advanced stage pT3+ disease (OR 1.68, 95% CI 1.14-2.47) while men with organ-confined high-grade (8-10) PC did not exhibit the same relationship. No significant associations were observed for men who were balding at age 40 years, given no balding at age 20. Men with androgenetic alopecia at age 20years are at increased risk of advanced stage PC. This small subset of men are potentially candidates for earlier screening and urological follow-up.

PPARGC1A and ADIPOQ polymorphisms are associated with aggressive prostate cancer in Mexican-Mestizo men with overweight or obesity.

Obesity constitutes a risk factor for the development of aggressive forms of prostate cancer. It has been proposed, that prostate cancer has a genetic predisposition and that PPARGC1A and ADIPOQ polymorphisms play a role in the development of this condition. To analyse the association of two PPARGC1A and ADIPOQ polymorphisms as well as their haplotypes, with the development of aggressive prostate cancer in Mexican-Mestizo men with overweight or obesity. Two hundred fifty seven men with prostate cancer of Mexican-Mestizo origin were included. Body mass index (BMI) was determined and the degree of prostate cancer aggressiveness by the D'Amico classification. DNA was obtained. Rs7665116 and rs2970870 of PPARGC1A, and rs266729 and rs1501299 of ADIPOQ were studied by real-time PCR allelic discrimination. Pairwise linkage disequilibrium, between single nucleotide polymorphisms was calculated and haplotype analysis was performed. A higher-risk (D'Amico classification) was observed in 21.8% of patients. An association of cancer aggressiveness with rs2970870 of PPARGC1A, and rs501299 of ADIPOQ, as well as with one haplotype of ADIPOQ was documented. This is the first study regarding the relationship of PPARGC1A and ADIPOQ polymorphisms, and the aggressiveness of prostate cancer in men with overweight or obesity.

Association of a TFAM haplotype with aggressive prostate cancer in overweight or obese Mexican Mestizo men

BackgroundMitochondrial dysfunction has been associated with the development of cancer and obesity, being prostate cancer more aggressive in obese men. It has been suggested that the mitochondrial transcription factor A (TFAM) plays a central role in these events. ObjectiveThe aim of this study was to analyze the possible association of 3 TFAM polymorphisms, as well as their haplotypes, with the development of aggressive prostate cancer in overweight or obese Mexican Mestizo men. Subjects and methodsA total of 257 unrelated men with histologically confirmed prostate cancer, of Mexican Mestizo ethnic origin, were included. Body mass index was determined and the degree of prostate cancer aggressiveness was demarcated by the D’Amico classification. DNA was obtained from blood leukocytes. The rs1937, rs1049432, and rs11006132, as well as their haplotypes, were studied by real-time polymerase chain reaction allelic discrimination. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated; haplotype analysis was performed. ResultsA higher risk (D’Amico classification) was documented in 56 patients (21.8%). We did not find a significant association among those polymorphisms analyzed; however, one haplotype was significantly associated with cancer aggressiveness. ConclusionsTo our knowledge, this constitutes the first study regarding the relationship of 3 TFAM polymorphisms, as well as their haplotypes, and the aggressiveness of prostate cancer in overweight or obese men; the most frequent haplotype was associated with cancer aggressiveness.

Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.

Interleukin-17 (IL-17) plays important roles in inflammation, autoimmune diseases, and some cancers. Obese people are in a chronic inflammatory state with increased serum levels of IL-17, insulin, and insulin-like growth factor 1 (IGF1). How these factors contribute to the chronic inflammatory status that promotes development of aggressive prostate cancer in obese men is largely unknown. We found that, in obese mice, hyperinsulinemia enhanced IL-17-induced expression of downstream proinflammatory genes with increased levels of IL-17 receptor A (IL-17RA), resulting in development of more invasive prostate cancer. Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. IL-17RA phosphorylation was reduced, while the IL-17RA levels were increased in the proliferative human prostate cancer cells compared to the normal cells. Insulin and IGF1 enhanced IL-17-induced inflammatory responses through suppressing GSK3, which was shown in the cultured cell lines in vitro and obese mouse models of prostate cancer in vivo. These findings reveal a mechanism underlying the intensified inflammation in obesity and obesity-associated development of aggressive prostate cancer, suggesting that targeting GSK3 may be a potential therapeutic approach to suppress IL-17-mediated inflammation in the prevention and treatment of prostate cancer, particularly in obese men.

Serum adiponectin concentration in 2,939 Japanese men undergoing screening for prostate cancer.

BackgroundRecent investigations suggest that serum adiponectin levels are negatively associated with the development of aggressive prostate cancer, however, not all epigenetic studies support the inverse association.MethodsWe analyzed serum adiponectin levels, prostate-specific antigen (PSA) levels, and outcomes of prostate cancer screening of 2,939 participants of a PSA-based screening program conducted by a single institute in Japan.ResultsThe median body mass index (BMI) of the participants was 23.9 kg/m2, and 31% had a BMI ≥ 25 kg/m2. The adiponectin levels were significantly and negatively correlated with BMI (r = −0.260, P < 0.0001). However, a significant and positive correlation was observed between adiponectin levels and PSA levels (r = 0.054, P = 0.0061). After screening, 24 (0.82%) patients were diagnosed with prostate cancer. Interestingly, the adiponectin levels of the 24 prostate cancer patients (average 9.86 μg/mL) were significantly higher than those of the 2,817 participants with PSA levels < 4 ng/mL (average 7.63 μg/mL) (P = 0.0049). However, when restricted to the eight high-risk prostate cancer patients, the adiponectin levels did not differ from those of the participants with PSA levels < 4 ng/mL. The age-adjusted cancer detection rate of the participants was calculated by stratifying the BMI (cut-off level 25 kg/m2) and adiponectin levels (cut-off level 6.7 μg/mL). The cancer detection rate in the high-BMI and high-adiponectin group was 1.67%, which was the highest among all groups.ConclusionsThere was a significant positive correlation between adiponectin levels and PSA levels. The present findings also suggest that the incidence of low- or intermediate-risk prostate cancer might be increased in overweight men with high serum adiponectin levels.

MP56-13 ADIPOSIS IS AN INDEPENDENT RISK-FACTOR FOR DEVELOPING HIGH-RISK PROSTATE CANCER - A PROSPECTIVE STUDY

INTRODUCTION AND OBJECTIVES: Both low serum testosterone levels and overweight have been reported to associated with advanced prostate cancer (PC) stage and grade. Even though the biological process underlying these observations is not yet fully understood. Moreover, serum testosterone levels and body composition are also known to be related. The aim of this study was to prospectively evaluate whether low testosterone levels, or obesity, or both are directly associated with stage/grade in patients with clinically localized PC. METHODS: Pre-operative sex hormone levels (total (tT) and free testosterone (fT), sexual hormone-binding globulin (SHBG), body mass index (BMI), waist circumference (WC) were prospectively assessed in 776 consecutive European Caucasian men treated with radical prostatectomy from February 2011 to October 2014. The results were had been related to patient specific and clinicopathologic data. RESULTS: Patients with BMI 30 kg/m (n1⁄4146) and WC 110 cm (highest quartile; n1⁄4210) were shown to be significantly associated with pathological tumor grade (Gleason Score >7; p1⁄40.012 and p pT2; p1⁄40.02). Patients with BMI 30 kg/m vs. 7) or extraprostatic disease (>pT2) or lymph node metastases. On multivariable logistic regression analysis, both BMI 30 kg/m (relative risk 2.266; 95% CI 1.169 e 4.391; p1⁄40.015) and WC 110 cm (relative risk 2.539; 95% CI 1.618 e 5.511; p 7) and WC 110 cm was associated significantly with lymph node metastases (relative risk 2.536; 95% CI 1.338 e 4.805; p1⁄40.004) after accounting for tT and age. CONCLUSIONS: This is the first study showing that obesity but not low serum testosterone levels is significantly associated with high grade and metastatic disease in men diagnosed with clinically localized PC. Our findings suggest that low androgen levels at diagnosis, which used to be held responsible for the development of aggressive PC, is only an epiphenomenon of obesity rather than the cause of PC development and/or progression.

MP56-14 PREDICTORS AND ONCOLOGIC OUTCOMES OF PT0 PROSTATE CANCER IN RADICAL PROSTATECTOMY SPECIMENS

INTRODUCTION AND OBJECTIVES: Both low serum testosterone levels and overweight have been reported to associated with advanced prostate cancer (PC) stage and grade. Even though the biological process underlying these observations is not yet fully understood. Moreover, serum testosterone levels and body composition are also known to be related. The aim of this study was to prospectively evaluate whether low testosterone levels, or obesity, or both are directly associated with stage/grade in patients with clinically localized PC. METHODS: Pre-operative sex hormone levels (total (tT) and free testosterone (fT), sexual hormone-binding globulin (SHBG), body mass index (BMI), waist circumference (WC) were prospectively assessed in 776 consecutive European Caucasian men treated with radical prostatectomy from February 2011 to October 2014. The results were had been related to patient specific and clinicopathologic data. RESULTS: Patients with BMI 30 kg/m (n1⁄4146) and WC 110 cm (highest quartile; n1⁄4210) were shown to be significantly associated with pathological tumor grade (Gleason Score >7; p1⁄40.012 and p pT2; p1⁄40.02). Patients with BMI 30 kg/m vs. 7) or extraprostatic disease (>pT2) or lymph node metastases. On multivariable logistic regression analysis, both BMI 30 kg/m (relative risk 2.266; 95% CI 1.169 e 4.391; p1⁄40.015) and WC 110 cm (relative risk 2.539; 95% CI 1.618 e 5.511; p 7) and WC 110 cm was associated significantly with lymph node metastases (relative risk 2.536; 95% CI 1.338 e 4.805; p1⁄40.004) after accounting for tT and age. CONCLUSIONS: This is the first study showing that obesity but not low serum testosterone levels is significantly associated with high grade and metastatic disease in men diagnosed with clinically localized PC. Our findings suggest that low androgen levels at diagnosis, which used to be held responsible for the development of aggressive PC, is only an epiphenomenon of obesity rather than the cause of PC development and/or progression.

β-Adrenergic Receptor Signaling in Prostate Cancer

Enhanced sympathetic signaling, often associated with obesity and chronic stress, is increasingly acknowledged as a contributor to cancer aggressiveness. In prostate cancer, intact sympathetic nerves are critical for tumor formation, and sympathectomy induces apoptosis and blocks tumor growth. Perineural invasion, involving enrichment of intra-prostatic nerves, is frequently observed in prostate cancer and is associated with poor prognosis. β2-adrenergic receptor (ADRB2), the most abundant receptor for sympathetic signals in prostate luminal cells, has been shown to regulate trans-differentiation of cancer cells to neuroendocrine-like cells and to affect apoptosis, angiogenesis, epithelial–mesenchymal transition, migration, and metastasis. Epidemiologic studies have shown that use of β-blockers, inhibiting β-adrenergic receptor activity, is associated with reduced prostate cancer-specific mortality. In this review, we aim to present an overview on how β-adrenergic receptor and its downstream signaling cascade influence the development of aggressive prostate cancer, primarily through regulating neuroendocrine differentiation.