Aggressive CaP Research Articles

Abstract 1881: Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African- and European-Americans

Abstract Background: Controversies remain over the safety and efficacy of vitamin E (α-tocopherol) supplement use for the prevention of prostate cancer (CaP); however, associations between different tocopherol forms and CaP aggressiveness have yet to be examined. This study examined whether food intake of tocopherols, vitamin E supplement use, and adipose tissue biomarkers of tocopherol were associated with CaP aggressiveness among African-American (AA) and European-American (EA) men with newly diagnosed CaP. Methods: Associations between tocopherols from diet, vitamin E supplement use, and adipose tissue tocopherol levels and CaP aggressiveness were examined in a large population-based, case-only study of incident CaP among AA (n = 1,023) and EA (n = 1,079) research subjects enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP). CaP aggressiveness was defined by a combination of clinical Gleason sum and stage and prostate-specific antigen (PSA) level at diagnosis as high aggressive (Gleason sum ≥8 or PSA >20 ng/mL, or Gleason sum ≥ 7 and cancer stage T3-T4); low aggressive (Gleason sum < 7 and stage T1-T2 and PSA<10 ng/ml); or intermediate aggressive CaP (all others). Dietary tocopherol intake was estimated from a food frequency questionnaire, supplement use from questionnaire/inventory, and biomarkers from abdominal adipose samples measured using high-performance liquid chromatography. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) comparing high aggressive CaP to low/intermediate aggressive CaP. Results: Higher dietary intakes of α- and δ-tocopherol were inversely and linearly associated with CaP aggressiveness among EAs [OR (95%CI), highest vs. lowest quartile: α-tocopherol 0.34 (0.17-0.69) Ptrend = 0.006; δ-tocopherol 0.45 (0.21-0.95) Ptrend = 0.007]. Dietary tocopherol levels were not associated with CaP aggressiveness among AAs. No significant associations were observed between supplemental vitamin E use and CaP aggressiveness among AAs or EAs. Mean adipose α-tocopherol concentrations were markedly higher in EAs (151.4 mcg/g) compared to AAs (86.6 mcg/g). No statistically significant associations between adipose α-tocopherol levels and high aggressive CaP were observed [OR (95%CI); highest versus lowest quartiles were for EAs 1.43 (0.66-3.11) and AAs 0.66 (0.27-1.62)]. Conclusions: These results add to the literature suggesting no obvious benefit from vitamin E supplement use in relation to CaP aggressiveness. Inverse associations between higher dietary sources of tocopherols and aggressive CaP among EAs suggest that diets high in tocopherols may contain additional protective components or may be a marker for an overall healthier lifestyle. Citation Format: Samuel Antwi, Susan E. Steck, L. Joseph Su, James R. Hebert, Hongmei Zhang, Elizabeth T. H. Fontham, Jeannette T. Bensen, James L. Mohler, Lenore Arab. Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African- and European-Americans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1881. doi:10.1158/1538-7445.AM2015-1881

Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP).

Controversies remain over the safety and efficacy of vitamin E (i.e., α-tocopherol) supplementation use for the prevention of prostate cancer (CaP); however, associations of different tocopherol forms and CaP aggressiveness have yet to be examined. This study examined whether food intake of tocopherols, vitamin E supplement use, and adipose tissue biomarkers of tocopherol were associated with CaP aggressiveness among African-American (AA, n = 1,023) and European-American (EA, n = 1,079) men diagnosed with incident CaP. Dietary tocopherols were estimated from a food frequency questionnaire, supplement use from questionnaire/inventory, and biomarkers from abdominal adipose samples measured using high-performance liquid chromatography. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated from logistic regression comparing high-aggressive CaP to low/intermediate aggressive CaP, adjusting for covariates. Dietary intakes of α-and δ-tocopherol were related inversely to CaP aggressiveness among EAs [OR (95%CI), highest versus lowest quartile: α-tocopherol, 0.34 (0.17-0.69), P(trend) = 0.006; δ-tocopherol, 0.45 (0.21-0.95) P(trend) = 0.007]. Inverse associations between dietary and supplemental α-tocopherol and CaP aggressiveness were observed among AAs, though these did not reach statistical significance [OR (95%CI), highest versus lowest quartile: dietary α-tocopherol, 0.58 (0.28-1.19), P(trend) = 0.20; supplemental α-tocopherol, 0.64 (0.31-1.21) P(trend) = 0.15]. No significant association was observed between adipose tocopherol levels and CaP aggressiveness [OR (95%CI), highest versus lowest quartiles of α-tocopherol for EAs 1.43 (0.66-3.11) and AAs 0.66 (0.27-1.62)]. The inverse associations observed between dietary sources of tocopherols and CaP aggressiveness suggests a beneficial role of food sources of these tocopherols in CaP aggressiveness.

Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP.

BackgroundAfrican Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs).MethodsPlasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either ‘high’ or ‘low’ aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis. Mean plasma 25(OH)D3 concentrations were compared by proportion of African ancestry. Logistic regression was used to calculate multivariable adjusted odds ratios (OR) and 95% confidence intervals (95%CI) for high aggressive CaP by tertile of plasma 25(OH)D3.ResultsAAs with highest percent African ancestry (>95%) had the lowest mean plasma 25(OH)D3 concentrations. Overall, plasma 25(OH)D3 was associated positively with aggressiveness among AA men, an association that was modified by calcium intake (ORT3vs.T1: 2.23, 95%CI: 1.26–3.95 among men with low calcium intake, and ORT3vs.T1: 0.19, 95%CI: 0.05–0.70 among men with high calcium intake). Among EAs, the point estimates of the ORs were <1.0 for the upper tertiles with CIs that included the null.ConclusionsAmong AAs, plasma 25(OH)D3 was associated positively with CaP aggressiveness among men with low calcium intake and inversely among men with high calcium intake. The clinical significance of circulating concentrations of 25(OH)D3 and interactions with calcium intake in the AA population warrants further study.

MP77-07 THE PREVALENCE OF PROSTATE BIOPSY GLEASON SCORE ≥ 7(3+4) EXCEEDS 40% IN YOUNG PUERTO RICAN MEN SCREENED FOR PROSTATE CANCER: A CASE FOR EARLY DETECTION BEFORE AGE 55 IN THIS POPULATION

You have accessJournal of UrologyProstate Cancer: Detection and Screening VI1 Apr 2015MP77-07 THE PREVALENCE OF PROSTATE BIOPSY GLEASON SCORE ≥ 7(3+4) EXCEEDS 40% IN YOUNG PUERTO RICAN MEN SCREENED FOR PROSTATE CANCER: A CASE FOR EARLY DETECTION BEFORE AGE 55 IN THIS POPULATION Patricia Maymi and Ricardo Sanchez-Ortiz Patricia MaymiPatricia Maymi More articles by this author and Ricardo Sanchez-OrtizRicardo Sanchez-Ortiz More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.547AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES While in US Census data only 8.0% of Puerto Ricans (PR) self−identified as “black or African American (AA)”, genomic admixture studies show that average West African ancestry gene values in PR range between 17 and 32%. These data, and the known association between aggressive prostate CaP cancer in AA men may help explain the higher observed CaP mortality in PR. Our goal was to evaluate the pathologic features of young PR men diagnosed through PSA screening to ascertain whether this population should be deemed high−risk and screened from age 40. METHODS Our CaP database was queried for men who diagnosed with asymptomatic CaP through PSA screening before age 55. Clinical variables were compared to men age 55 and older. All slides were reviewed by a pathologist trained at an NCCN−designated cancer center. Statistical analysis was performed with SPSS. RESULTS Of 606 patients, 183 men were identified age≤55 years (yrs.) (mean: 49.7 years, range 38 to 54). Mean serum PSA was 5.7 ng/ml, percent clinical stage T1c: 79.7%, and mean prostate size was 42.7 cc. Patients had undergone prostate biopsies with a mean number of 11.7 cores and a mean of 2.97 positive cores (range 1 to 14). On biopsy, 43.1% (79/183) of men had evidence of Gleason score ≥7(3+4). Patients younger than 55 (Y) were more likely to have a first−degree relative with CaP than older men (28% Y vs. 19.4%, p<0.01) but less likely to have smoked (22.8% Y vs. 33.3%, p< 0.02), have diabetes (9.4% Y vs. 19.6%, p <0.01), hypertension (34.8% Y vs. 58.7%, p< 0.01), a higher clinical stage (T1c 79.7% Y vs. 71.2%, p<0.03), or Gleason score ≥7 on biopsy (43.1% Y vs. 56.4%, p<0.02). There were no significant differences between young and older men with regards to serum PSA (5.7 ng/ml Y vs. 6.1 ng/ml), longest tumor length in any core per side (4.3 mm Y vs. 4.5 mm), total sum of tumor length per side (8.9 mm Y vs. 8.5 mm), percent positive cores (26.3% Y vs. 27.1%), or BMI (28.5 Y vs. 28.2). CONCLUSIONS In this series of Puerto Rican men found to have CaP through early detection, patients <55 yrs. exhibited a 43% risk of harboring Gleason score≥7(3+4) on biopsy. Furthermore, despite a lower prevalence of palpable disease than older patients, younger men exhibited no difference with regards to serum PSA, longest tumor length, total tumor sum in millimeters, and percent positive biopsies, traditional surrogates for tumor volume. These data support the concept that, similar to AA patients, discussions regarding early detection in Puerto Rican men should begin at age 40. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e995 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patricia Maymi More articles by this author Ricardo Sanchez-Ortiz More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract B08: Occupational and recreational physical activity in relation to prostate cancer aggressiveness: The North Carolina-Louisiana Prostate Cancer Project (PCaP)

Abstract Background: Physical activity (PA) has been implicated in the etiology of prostate cancer (CaP). However, there are considerable inconsistencies in the epidemiological literature. This may be due to failure to examine associations by CaP aggressiveness. While most men will develop CaP if they live long enough, usually the disease is indolent; only aggressive disease is of prognostic relevance. Methods: Associations of occupational and recreational PA in relation to CaP aggressiveness at diagnosis were examined in a large population-based, case-only study of incident CaP among African-American (n = 1,023) and European-American (n = 1,079) men (the North Carolina-Louisiana Prostate Cancer Project, PCaP). Men were classified as highly aggressive cases if Gleason sum =&amp;gt; 8 or PSA &amp;gt;20ng/ml or Gleason score =&amp;gt; 7 and clinical stage T3-T4 (N = 370, 18%). All others (low and intermediate aggressive cases) were classified as the comparison group. Recreational PA was measured using a validated questionnaire and occupational PA was estimated based on current and longest-held job titles. Metabolic equivalents (MET) were estimated for recreational PA and job titles using the Compendium of Physical Activities. Associations between CaP aggressiveness at diagnosis and PA were assessed using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age, race, body mass index, CaP screening history, smoking status, and energy intake. Additional adjustment for educational status was done for the occupational PA models. Results: Recreational PA, particularly walking for 75-150 minutes/week for exercise was associated with 33% lower odds of high aggressive CaP compared to no walking for exercise (OR= 0.67, 95% CI: 0.46-0.98). MET-hours/week from walking for exercise was inversely related to CaP aggressiveness, though did not reach statistical significance (OR= 0.77, 95% CI: 0.57-1.04, highest vs. lowest tertile; Ptrend = 0.08). PA at current job was associated with 28% lower odds of high aggressive CaP (OR= 0.72, 95% CI: 0.54-0.95, highest MET tertile vs. lowest). Conversely, the highest accumulation of PA at longest-held job (&amp;gt;132 MET-years) was associated with 61% higher odds of presenting with high aggressive CaP compared to 60-90 MET-years (OR=1.61, 95% CI: 1.08-2.40). There was no evidence of interaction between PA and race on the association with aggressive CaP. Conclusions: Walking for exercise and higher PA at current job were associated with reduced odds of high aggressive CaP. The positive association between highest PA at longest-held job and CaP aggressiveness may be influenced by residual confounding by low socioeconomic status, which often correlates with unhealthy lifestyle factors, such as poor diet. Funding: PCaP is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. Citation Format: Samuel Antwi, Susan E. Steck, L. Joseph Su, Bonny Blackard, Swann Arp-Adams, James R. Hebert, Elizabeth TH Fontham, Jeannette Bensen, James L. Mohler, Lenore Arab. Occupational and recreational physical activity in relation to prostate cancer aggressiveness: The North Carolina-Louisiana Prostate Cancer Project (PCaP). [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B08. doi:10.1158/1538-7755.DISP13-B08

Abstract 4038: Human prostate cancer invasion could be suppressed by 5-Aza-2′-deoxycytidine which can inhibit the TGF-β induced DNA methyltransferase (DNMT)

Abstract Introduction and Objective: We previously reported that loss of sensitivity to TGF-ß growth inhibition is partially due to promoter methylation and subsequent down regulation of TGF-ß receptors (TßRs) expression; a characteristic of aggressive PCa phenotypes. In this study, we address whether TGF-ß induced DNMT expression contributes to its receptors promoter methylation and loss of sensitivity to this cytokine, and a more agressive phenotype. We also explored the effects of 5-Aza-2′-deoxycytidine (5-Aza), a DNMT inhibitor, on CaP cell invasion. Methods: PC3 human PCa line and its variants with different invasive abilities were used. Expression of TßRs, DNMT and vimentin under the treatment of TGF-ß (10ng/mL), or 5-aza was evaluated by Western Blot and Real-Time PCR analysis. Methylation specific PCR (MSP) was performed to evaluate the status of TßRs promoters. Matrigel cell invasion assays were conducted using a 24-well transwell chamber (8-um pore size). Four different treatment groups were assigned to each cell line: Group 1- no treatment (control); Group 2- treatment with TGF-ß (10ng/mL) for 24 hours; Group 3- treatment with 5-Aza (2 µg/ml) for 24 hours; and Group 4- treatment with TGF-ß plus 5-Aza for 24 hours. The invaded cells were stained and counted under high magnification objective (100x). [3H] Thymidine incorporation assay were used to evaluate cell growth under the treatment of 5-Aza. Results: Both TßRI and TßRII expresion was significantly increased (2-2.5 folds) after treatment with 5-Aza in PC-3 cells. In contrast, treatment of TGF-ß signficantly increased the expression of DNMT by 3.2 fold and suppressed the expression of TßRI and TßRII by 46% and 29% respectively. This suppression and promoter methylation was recovered following treatment with 5-Aza. 5-Aza treatment also resulted in a significant inhibition of cell proliferation, regardless of whether cells were exposed to exogenous TGF-ß. An average of 82 cells/field were found to invade in the control group (Group 1). In Group 2, there was a significant increase in the number of invaded cells (139/field) with TGF-β treatment. Invasion of PC-3 cells was significantly inhibited by treatment of 5-aza, (only 10 /field). After treatment with 5-Aza, the expression of vimentin decreased by 50% fold, as well as DNMTs was inhibited significantly. Conclusion: Tumor derived TGF-ß-induced DNMTs mediates promoter hypermethylation and downregulation of its receptors of its own receptors. Knockdown of DNMT by 5-aza result in the demethylation of the TGF-ß receptors gene promoters, restoration of TGF-ß inhibition of cell growth, and inhibition of invasion of CaP cells by inhibiting the expression of DNMT and vimentin induced by TGF-ß. This results indicated 5-Aza may be a candidate for novel antitumor metastasis strategies in men with aggressive CaP. Citation Format: Qiang Zhang, Brian Helfand, Xiao Lin, Thomas Jang, Yinglu Guo, Janardan Khandekar, Timothy Michael Kuzel, Chung Lee. Human prostate cancer invasion could be suppressed by 5-Aza-2′-deoxycytidine which can inhibit the TGF-β induced DNA methyltransferase (DNMT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4038. doi:10.1158/1538-7445.AM2014-4038

Abstract 4212: ADAM10/Kuzbanian is upregulated during neuroendocrine prostate carcinogenesis

Abstract Prostate cancer (CaP) is the second leading cause of cancer death in men. Advanced prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Currently, androgen deprivation is the first line of therapy for metastatic CaP. However, CaP often progresses to an androgen-independent bone-metastatic stage, at which point chemotherapy and radiotherapy become the primary therapeutic options. Despite recent advances in therapeutic strategies, many cancers still develop resistance to radiation and therapies, making the identification of new therapies essential to improve the lives and survival rates of patients. We have studied neuroendocrine cancer progression in the cryptdin-2 SV40-TAg (CR2-TAg) mouse model of CaP. Since these cancers do not express androgen receptor, they are refractory to androgen therapy. Therefore, we sought new potential targets. We previously found that matrix metalloproteinases (MMPs), which are capable of degrading many extracellular matrix proteins and cell surface receptors, are upregulated during CR2-Tag tumor progression. In the present study, we examined expression of a family of a disintegrin and metalloproteinases (ADAMs) that is actively involved in these signaling pathways due to their role in releasing the extracellular domain of transmembrane proteins. ADAMs contain features of both adhesive proteins and proteinases. ADAM10 activates the epidermal growth factor receptor (EGFR) and NOTCH signaling systems controlling cell growth, invasion, and metastasis. We found that ADAM10 expression increased during tumor progression and was highly penetrant. We are quantifying the expression levels and localization patterns of ADAM10 in these samples over time. Since MMPs, like ADAMs, are capable of degrading many extracellular matrix proteins and cell surface receptors, we determined if MMPs (MMP 2, 7, and 9) contribute to ADAM10 expression or localization in aggressive hormone refractory CaP. We have stained for ADAM10 in tissue sections from the CR2-TAg mice that are each missing expression of MMPs to determine if that particular MMP contributes to ADAM10 expression or localization. Our research using ADAM10 localization as a potential biomarker and therapeutic target has potential clinical value to identify aggressive CaP earlier in patients. Our study of MMPs and their role in ADAM10 expression will offer insight into the mechanisms of advanced prostate tumor progression. Note: This abstract was not presented at the meeting. Citation Format: Brian D. Shannon, Laurie E. Littlepage. ADAM10/Kuzbanian is upregulated during neuroendocrine prostate carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2014-4212

¿Es la obesidad un factor predictor de agresividad en cáncer de próstata?

AimsTo describe the relation between obesity and prostate cancer (CaP) aggressiveness in a Mexican population. MethodsData was collected retrospectively from the electronic medical files of 167 patients with CaP. They were grouped according to body mass index (BMI), age, Gleason score, clinical stage, and D’Amico classification. The variables were correlated (BMI, prostate-specific antigen [PSA], clinical stage, Gleason score) and were analyzed using statistical models. ResultsA total of 167 patients with CaP were studied. The mean age was 69.4 years and mean pre-biopsy PSA was 25.36ng/m. Overweight was present as Grade I and Grade II obesity in 45% and 22.75% of the patients, respectively, and 25.7% were within their normal weight range. A total of 41.9% of the patients had a Gleason score of 6 and 47.9% of the tumors were classified as stage cT1c. According to the D’Amico classification, 11.37% of the patients were considered at low risk for aggressive CaP, 23.95% at intermediate risk, and 64.67% were at high risk. Those patients with a BMI > 25kg/m2 presented with a greater risk for high-risk CaP (OR 1.027; P=.46) and those with a BMI>25kg/m2 had a greater risk for a Gleason score of 8-10 (OR 1.310; P=.23). We identified a relation between BMI>25kg/m2 and PSA<20ng/mL (OR 1.14; P=.36) and a negative association between BMI>25kg/m2 and PSA>20ng/mL (OR 0.87; P=.35). No significant difference was found between BMI and clinical stage (OR 0.89; P=0.15). ConclusionsObese patients are at a higher risk for aggressive CaP; they presented with a lower PSA and the overweight and obese patients had a higher Gleason score. These data will enable us to make better preventive and therapeutic decisions in overweight and obese men with CaP.

Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells.

Impaired PTEN function is a genetic hallmark of aggressive prostate cancers (CaP) and is associated with increased CXCL8 expression and signaling. The current aim was to further characterize biological responses and mechanisms underpinning CXCL8-promoted progression of PTEN-depleted prostate cancer, focusing on characterizing the potential interplay between CXCL8 and other disease-promoting chemokines resident within the prostate tumor microenvironment. Autocrine CXCL8-stimulation (i) increased expression of CXCR1 and CXCR2 in PTEN-deficient CaP cells suggesting a self-potentiating signaling axis and (ii) induced expression of CXCR4 and CCR2 in PTEN-wild-type and PTEN-depleted CaP cells. In contrast, paracrine CXCL8 signaling induced expression and secretion of the chemokines CCL2 and CXCL12 from prostate stromal WPMY-1 fibroblasts and monocytic macrophage-like THP-1 cells. In vitro studies demonstrated functional co-operation of tumor-derived CXCL8 with stromal-derived chemokines. CXCL12-induced migration of PC3 cells and CCL2-induced proliferation of prostate cancer cells were dependent upon intrinsic CXCL8 signaling within the prostate cancer cells. For example, in co-culture experiments, CXCL12/CXCR4 signaling but not CCL2/CCR2 signaling supported fibroblast-mediated migration of PC3 cells while CXCL12/CXCR4 and CCL2/CCR2 signaling underpinned monocyte-enhanced migration of PC3 cells. Combined inhibition of both CXCL8 and CXCL12 signaling was more effective in inhibiting fibroblast-promoted cell motility while repression of CXCL8 attenuated CCL2-promoted proliferation of prostate cancer cells. We conclude that tumor-derived CXCL8 signaling from PTEN-deficient tumor cells increases the sensitivity and responsiveness of CaP cells to stromal chemokines by concurrently upregulating receptor expression in cancer cells and inducing stromal chemokine synthesis. Combined chemokine targeting may be required to inhibit their multi-faceted actions in promoting the invasion and proliferation of aggressive CaP.

MP12-18 FOCAL THERAPY FOR PROSTATE CANCER: THE UTILITY OF A CONFIRMATORY TRANSPERINEAL TEMPLATE GUIDED PROSTATE BIOPSY TO IDENTIFY APPROPRIATE CANDIDATES

You have accessJournal of UrologyImaging/Radiology III1 Apr 2014MP12-18 FOCAL THERAPY FOR PROSTATE CANCER: THE UTILITY OF A CONFIRMATORY TRANSPERINEAL TEMPLATE GUIDED PROSTATE BIOPSY TO IDENTIFY APPROPRIATE CANDIDATES Khanh Pham, Claudio Jeldres, John Corman, Katherine Odem-Davis, Erika Wolff, and Christopher Porter Khanh PhamKhanh Pham More articles by this author , Claudio JeldresClaudio Jeldres More articles by this author , John CormanJohn Corman More articles by this author , Katherine Odem-DavisKatherine Odem-Davis More articles by this author , Erika WolffErika Wolff More articles by this author , and Christopher PorterChristopher Porter More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.453AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Focal Therapy (FT) is considered a promising potential treatment option for men with low risk prostate cancer (CAP). FT may not be suitable for men with high volume, multifocal and high Gleason (GL) grade disease. The current standard to determine low risk CAP is 12-core transrectal ultrasound prostate biopsy (TRUS BX). We had 2 aims: 1. Determine the accuracy of a confirmatory staging 24-core transperineal template guided prostate biopsy (TP BX) 2. Evaluate the efficacy of TP BX to identify candidates for FT. METHODS For both aims we used an IRB approved prospective database to evaluate 172 men who underwent 24-core TP BX between 1/2009 and 8/2013. For Aim 1: Men with CAP who underwent 24-core TP BX and were treated with RP were evaluated. For Aim 2: Men who were candidates for FT based on an initial 12-core TRUS BX that demonstrated NCCN guideline low risk (cT1-2a, GL grade 6, PSA < 10), unifocal (< 2 positive cores) CAP were evaluated. Confirmatory 24-core TP BX was performed 3 months after initial TRUS BX under anesthesia using gray scale TRUS combined with the brachy-stepper device. The template included 12 cores obtained from the anterior prostate (base, mid and apex) together with 12 posterior lateral cores (base, mid and apex). RESULTS For Aim 1: 25 men had TP BX followed by RP. GL grade at TP BX significantly agreed with RP for 21/25 men; accuracy = 0.8 (95% CI: 0.59, 0.93; p=0.004). At RP, 23/25 men had anterior tumor (AT). TP BX sensitivity to RP detection of AT = 0.57 (95% CI: 0.34, 0.77; p=0.67). For Aim 2: 46 men met inclusion criteria. Following TP BX: 16 men demonstrated upgraded pathology with an estimated risk of 0.35 (95% CI: 0.21, 0.50), 20 men had increased volume of disease with an estimated risk of 0.44 (95% CI: 0.29, 0.59) and 30 men had multifocal tumors with an estimated risk of 0.65 (95% CI: 0.50, 0.79). Table 1 lists detailed results of TP BX. All 23 men (50%) with upgraded pathology or increased volume also had multifocal tumors detected. CONCLUSIONS Our analysis of carefully performed TP BX in men eligible for FT by TRUS BX indicates that TP BX accurately indicates GL Grade (0.8), and up to 50% of patients considered for FT have more aggressive multifocal CAP. While our results require confirmation in larger series, we believe TP BX may be important in men considering FT for low risk CAP. Table 1. Grade, Volume, Multifocality and Anteriorly Located Disease Following 24-Core TP Biopsy for Men Identified with Low Risk CAP by 12-Core TRUS Biopsy (N=46) Gleason Grade N (%) Mean PSA Mean PSAD Increased Volume N (%) Multifocal Disease N (%) Anteriorly Located Disease N (%) 3+3=6 30 (65) 5.2 0.12 7 (15) 14 (30) 15 (33) 3+4=7 11 (24) 8.4 0.17 8 (19) 11 (24) 10 (22) 4+3=7 1 (2) 7.4 0.16 1 (2) 1 (2) 1 (2) 4+4=8 1 (2) 5.0 0.20 1 (2) 1 (2) 1 (2) 4+5=9 2 (4) 6.7 0.13 2 (4) 2 (4) 2 (4) 5+4=9 1 (2) 4.5 0.14 1 (2) 1 (2) 1 (2) © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e112-e113 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Khanh Pham More articles by this author Claudio Jeldres More articles by this author John Corman More articles by this author Katherine Odem-Davis More articles by this author Erika Wolff More articles by this author Christopher Porter More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

MP49-11 THE RHOA EFFECTOR PROTEIN KINASE N1 AS A TARGET FOR SELECTIVE ANDROGEN DEPRIVATION THERAPY

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-11 THE RHOA EFFECTOR PROTEIN KINASE N1 AS A TARGET FOR SELECTIVE ANDROGEN DEPRIVATION THERAPY Adam DePriest, Kelly Duncan, Elena Pop, James Mohler, and Hannelore Heemers Adam DePriestAdam DePriest More articles by this author , Kelly DuncanKelly Duncan More articles by this author , Elena PopElena Pop More articles by this author , James MohlerJames Mohler More articles by this author , and Hannelore HeemersHannelore Heemers More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1112AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The androgen receptor (AR) is the principal target for treatment of advanced prostate cancer (CaP). Androgen deprivation therapy (ADT) inhibits systemic AR action, but is not curative and causes severe side effects. The development of more effective and selective forms of ADT requires insights in the molecular mechanisms by which AR governs CaP progression. Our group has identified a novel mode of androgen action in which effects of androgens are mediated by Serum Response Factor (SRF). This mechanism controls a very small fraction of androgen action that is associated with aggressive CaP behavior. Androgen control over SRF action is achieved via androgen activation of the small GTPase RhoA. Here, the signal transduction that conveys androgen-responsiveness from RhoA to SRF, and its potential for selective inhibition of SRF-mediated androgen action, is identified. Methods An siRNA screen was performed to identify the RhoA effector protein(s) that mediates signaling from androgen-activated RhoA to SRF. qRT-PCR, custom oligoarray, promoter-reporter transfection and Western blotting approaches were used to study androgen-responsiveness of Androgen Response Element (ARE)-driven AR target genes or CArG box-driven SRF target genes. Androgen-stimulated (AS) and castration-recurrent (CR) CaP cells were treated with siRNAs targeting the RhoA effector Protein Kinase N1 (PKN1) or the PKN1 inhibitor lestaurtinib. Validation studies involved CaP cell lines that (over)express wild-type RhoA, dominant-active RhoA, dominant-negative RhoA, wild-type PKN1, or PKN1 forms mutated in its kinase domain or RhoA-interacting regions. Results The RhoA effector PKN1 was isolated as key mediator of androgen-responsive SRF action. PKN1 is overexpressed in CaP, where its overexpression has been correlated with CaP dedifferentiation. Loss of PKN1 decreased the androgen-responsiveness of SRF target genes, but affected androgen regulation of only 12 of 452 (or 2.6%) of ARE-driven genes. PKN1-dependent androgen regulation of SRF target genes was maintained in AS and CR CaP cells and in CaP cells that overexpress wild-type or dominant-active RhoA. Mutation of PKN1’s kinase domain or RhoA interaction sites attenuated androgen regulation of SRF target genes. PKN1 inhibitor lestaurtinib preferentially impeded androgen regulation of SRF target genes over that of ARE-driven genes. Conclusions PKN1 inhibitors may represent more selective forms of ADT that affect only androgen-dependent events that underlie CaP progression. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e506 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Adam DePriest More articles by this author Kelly Duncan More articles by this author Elena Pop More articles by this author James Mohler More articles by this author Hannelore Heemers More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Androgen-responsive Serum Response Factor target genes regulate prostate cancer cell migration

Progression of prostate cancer (CaP) relies on androgen receptor (AR) signaling, but AR-dependent events that underlie the lethal phenotype remain unknown. Recently, an indirect mechanism of androgen action in which effects of AR on CaP cells are mediated by Serum Response Factor (SRF) has been identified. This is the first mode of androgen action to be associated with aggressive CaP and disease recurrence. The manner in which androgen-responsive SRF activity controls aggressive CaP cell behavior is unknown. Here, the contribution of two representative SRF effector genes that are underexpressed, calponin 2 (CNN2), or overexpressed, sidekick-homolog 1 (SDK1), in clinical CaP specimens is studied. AR- and SRF- dependency of CNN2 and SDK1 expression was verified using synthetic and natural androgens, antiandrogens, and small interfering RNAs targeting AR or SRF, and evaluating the kinetics of androgen induction and SRF binding to endogenously and exogenously expressed regulatory gene regions in AR-positive CaP model systems that mimic the transition from androgen-stimulated to castration-recurrent disease. Small interfering RNA-mediated deregulation of CNN2 or SDK1 expression did not affect CaP cell proliferation or apoptosis but had marked effects on CaP cell morphology and actin cytoskeleton organization. Loss of CNN2 induced cellular protrusions and increased CaP cell migration, whereas silencing of SDK1 led to cell rounding and blunted CaP cell migration. Changes in cell migration did not involve epithelial-mesenchymal transition but correlated with altered β1-integrin expression. Taken together, individual androgen-responsive SRF target genes affect CaP cell behavior by modulating cell migration, which may have implications for therapeutic intervention downstream of AR and SRF.

ABCD3 Gene Important In Prostate Cancer

African American men have higher rates of prostate cancer morbidity and mortality than men of other racial or ethnic groups in the US and globally. We favor genetics as the factor that explains prostate cancer health disparity in Black men. The objective of our study was to interrogate cDNA microarray data comparing gene expression profiles in AA and EA to hunt for gene or gene signatures that are associated with aggressive Prostate cancer. Bioinformatic interrogation of our genomic microarray data identified ABCD3 expression as significantly associated with African American prostate tumors. Our findings implicated involvement of three network hubs, centered on ERK, Mapk and NFkB signaling pathways. We further demonstrated that ABCD3 expression increased with increasing metastatic potential in a panel of novel CaP cells lines. We observed increased ABCD3 expression in more aggressive tumors compared to normal prostate tissue in a large patient cohort. Lastly si‐ABCD3 treatment in MDA‐PC‐2b cells resulted in a significant decrease in proliferation as well as enhanced chemosensitivity to Paclitaxel. Thus, ABCD3 appears to play an important role in aggressive CaP progression.

Polymorphisms in fragile histidine triad gene (FHIT) associated with aggressive prostate cancer and cancer specific mortality.

4646 Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase known to promote apoptosis responding to DNA damage in epithelial cells. It resides in the most frequently observed fragile site in the human genome, FRA3B, and is frequently deleted in early development of multiple cancer types. More importantly, down regulation of FHIT protein has been associated with clinical features of tumors, such as the presence of extraprostatic extension and Gleason Score &gt; 8 in prostate cancer (CaP), advanced diseases in breast cancer, and shorter survival after platinum-based treatment for advanced non-small cell lung cancer. Previously, a genetic locus for CaP has been reported in FHIT. Here we evaluated association of aggressive CaP and death due to CaP with Single nucleotide polymorphisms (SNPs) in FHIT using cases and controls of European origin nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason &lt; 7 and stage &lt; III; 688 with aggressive CaP, Gleason &gt;= 7 and/or stage III/IV; 63 with death due to CaP) and 1,167 controls using an incidence density sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic regression were performed to test association. Results: We detected significant association (p &lt; 0.05) of incident CaP to 48 SNPs and aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a 7 kb region, one for incident CaP and the other for aggressive CaP, remained marginally significant (corrected p = 0.053 and 0.093, respectively). The same risk allele for aggressive CaP was also associated with CaP-specific mortality (OR = 1.50, p = 0.027). The association was stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment options after diagnosis. Test on imputed SNPs within the 7 kb intronic region identified 7 additional SNPs in 2 linkage disequilibrium groups at higher risk to CaP-specific death (OR = 1.98, p = 0.00015 and OR = 2.51, p = 0.0027). Conclusions: Risk SNPs in FHIT were implicated for aggressive disease and CaP specific death. Replication of these SNPs in other populations is warranted.

Coffee Consumption and Prostate Cancer Aggressiveness Among African and Caucasian Americans in a Population-Based Study

This study evaluated the relationship between caffeinated and decaffeinated coffee and prostate cancer (CaP) aggressiveness using data from a population-based incident CaP study within the North Carolina-Louisiana Prostate Cancer Project (PCaP). Classification of CaP aggressiveness at diagnosis was based on clinical criteria for 1,049 African-American (AA) and 1,083 Caucasian-American (CA) research subjects. Coffee consumption was measured using a modified NCI Dietary History Questionnaire. No significant associations were found between CaP aggressiveness and consumption of either caffeinated or decaffeinated coffee. The OR for high aggressive CaP among consumers of more than 4 cups per day was 0.92 (95%CI = 0.61, 1.39), compared to non-coffee-drinkers. Results stratified by race found no significant associations and no noticeable trends in either AAs (P for trend = 0. 62) or CAs (P for trend = 0.42). In contrast to a recent report on a select population that has less complete information on CaP aggressiveness suggesting that coffee prevents aggressive CaP, this rapid case ascertainment population-based study, in a biracial population with differing risks of CaP did not demonstrate a protective relationship between high coffee consumption and risk of high aggressive CaP.

348 POPULATION-BASED DESCRIPTIVE ANALYSIS OF PROSTATE CANCER DEATHS OVER AN 18-YEAR PERIOD

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History II1 Apr 2012348 POPULATION-BASED DESCRIPTIVE ANALYSIS OF PROSTATE CANCER DEATHS OVER AN 18-YEAR PERIOD Brock Oneil, Christopher Dechet, Robert Stephenson, and William Lowrance Brock OneilBrock Oneil Salt Lake City, UT More articles by this author , Christopher DechetChristopher Dechet Salt Lake City, UT More articles by this author , Robert StephensonRobert Stephenson Salt Lake City, UT More articles by this author , and William LowranceWilliam Lowrance Salt Lake City, UT More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.409AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Much of the scientific literature on prostate cancer (CaP) focuses on screening, diagnosis, treatment and quality of life outcomes. Little is written about those who die from CaP. In this study, we sought to provide descriptive data about men who die from CaP to better understand how they initially present and are treated. METHODS Data were obtained from the Surveillance Epidemiology and End Results (SEER) dataset for men older than 40 years who were diagnosed with and died from CaP between 1990 and 2008. We present patient demographics, initial pathologic features, and primary treatment within 6 months of diagnosis. As more detailed pathologic data are available from SEER after 2004, we conducted a subgroup analysis including only men who were diagnosed with and died of CaP during this time frame. RESULTS Demographics: 60,139 patients met inclusion criteria. The median age at diagnosis was 74 years (interquartile range (IQR) 67-81) and median age at death was 79 years (IQR 71-85). Time from diagnosis to death ranged from <1 month to 225 months, with a median of 34 months (IQR 13-71). Diagnostic Information PSA was elevated in nearly all patients at diagnosis (93%). Of those with Gleason score available at diagnosis, most had a score 8 or greater (56%). Thirty-eight percent had a Gleason score between 5 and 7. The below table shows Gleason results from the subgroup. Primary and Secondary Gleason Patterns for Patients Diagnosed After January 1, 2004 (n=4801) Primary Pattern 3 4 5 Secondary Pattern Total 3 9% 10% 2% 21% 4 11% 17% 14% 42% 5 3% 25% 10% 38% Total 23% 52% 26% * Total percentages > 100% because of rounding. Treatment Most patients did not undergo any surgery (66%) within 6 months of diagnosis. An additional 24% had surgery for palliative or diagnostic reasons only. Surgery with curative intent was received by 10%. Approximately 27% had primary radiation therapy. CONCLUSIONS This descriptive analysis reveals that most men who died from CaP were older, had aggressive disease, and underwent limited therapy. Part of this effect is likely due to an influence of our methodology, which favors aggressive CaP. Yet, more than a quarter of these men were 70 or younger at diagnosis, nearly half had Gleason 7 or less disease, and some had therapy aimed at cure. Furthermore, in the subgroup, a cohort even more influenced by our methodology to favor advanced CaP, almost 10 % had low risk disease (Gleason 3+3=6). Analyses such as these improve our understanding of who is dying from CaP and may help identify areas of further study for the detection and treatment of this disease. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e141-e142 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brock Oneil Salt Lake City, UT More articles by this author Christopher Dechet Salt Lake City, UT More articles by this author Robert Stephenson Salt Lake City, UT More articles by this author William Lowrance Salt Lake City, UT More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

The effect of acute and chronic exposure to acetaldehyde—a mutagenic metabolite of dietary ethanol—on prostate cancer cells: A potential source of race disparity disfavoring black men.

143 Background: We recently reported that the ADH1B*3 allele, which is specific to African Americans (AA), when combined with ethanol intake may constitute a gene-environment interaction leading to elevated prostate cancer (CaP) and potentially aggressive CaP risk among AA men possibly through intra-prostatic acetaldehyde accumulation. Indeed, studies have shown microsomes from rat ventral prostates biotransform ethanol to acetaldehyde that further metabolizes into oxidative stress-inducing acetyl radicals. In addition, acetaldehyde has been previously shown to enhance proliferation of colon cancer cells. Whether acetaldehyde has the same effect on CaP is unknown. Methods: We subjected DU-145 CaP cells to varying concentrations of acetaldehyde using acute and chronic models of exposure and measured tumor proliferation using MTS assay. Proliferation was measured over 4 days of acetaldehyde treatment in acute and after 2 weeks of treatment in chronic exposure experiments. All experiments were conducted in triplicate. Results were expressed as mean values for each treatment referenced to untreated cells. Doubling times were calculated using least squares fitting exponential regression. Results: In the acute exposure model, proliferation of DU-145 cells was inhibited by 150 uM acetaldehyde by 28% while 1,500uM and higher concentrations resulted in complete inhibition of proliferation. After chronic exposure to acetaldehyde, proliferation of DU-145 cells was inhibited by 500 uM acetaldehyde by 19%. In contrast, chronic exposure with 1,000 uM acetaldehyde resulted in increased proliferation by 9% and shortened tumor doubling time. Conclusions: Acute exposure to acetaldehyde resulted in inhibition of CaP cellular proliferation. Chronic exposure to high acetaldehyde concentrations promoted tumor proliferation likely through selection for more robust CaP cells that survive the repeated chemical insult. Our results suggest that chronic acetaldehyde exposure of existent CaP may potentially promote disease aggressiveness. Uncovering mechanisms for enhanced CaP cell proliferation by acetaldehyde are warranted.

TGF-β regulates DNA methyltransferase expression in prostate cancer, correlates with aggressive capabilities, and predicts disease recurrence.

BackgroundDNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.Methodology/Principal FindingsWe used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Conclusions and SignificanceOur findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.

Detecting gene-gene interactions in prostate disease in African American men

BackgroundThe most common male malignancy in the United States is prostate cancer; however its rate of occurrence varies significantly among ethnic groups. In a previous cDNA microarray study on CaP tumors from African American (AA) and Caucasian (CA) patients, we identified 97 candidate genes that exhibited opposite gene expression polarity with respect to race groups; genes up-regulated in AA were simultaneously down-regulated in CA.PurposeThe purpose of this study was to narrow the 97 member gene list, to a smaller number of genes in order to focus studies on a limited number of genes/SNPs that might explain prostate cancer disparity in African Americans.MethodsWe performed genotype-phenotype, SNP and expression transcript levels correlations using HapMap Yoruba population with 85 of our 97 prostate candidate genes using SCAN database.ResultsFindings revealed an association of SNPs surrounding ABCD3 gene with basal gene expression of RanGAP1 is important in prostate tumors in AA. Hence, to confirm our results in clinical biospecimen, we monitored expression of ABCD3 in a novel panel of African American and Caucasian prostate cancer paired cell lines. The LNCaP, C4-2B showed 2-fold increase; MDA-2PC-2B cell line, derived from AA, showed highest fold-change, 10-fold. The EGFR over expressing DU-145 WT cell line exhibited a 4-fold increase in expression relative to non transfected DU-145 prostate cell lines. Furthermore, Ingenuity Network analysis implicated our AA prostate candidate genes are involved in three network hubs, ERK, MapK and NFkB pathways.ConclusionsTaken together, these findings are intriguing because other members of the ABC gene family, namely, ABCC3, ABCD1, and ABCD2 have been shown to confer chemoresistance in certain cancer types. Equally important, is the fact that activation of the MapK/ERK pathway via EGFR stimulation is vital for increased transcription of numerous cancer related genes. It is especially noteworthy that overexpression of EGFR has been widely observed in AA prostate tumors. Collectively our findings lead us to think that a novel signaling cascade, through which increased aggressiveness and chemoresistance is achieved, may explain prostate cancer health disparity in AA males and the nature of aggressive CaP tumors in general.

HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer

Prostate cancer (CaP) is the most common cancer among adult men in the Western world. Better insight into its tumor-activating pathways may facilitate the development of targeted therapies. In this study, we show that patients who develop prostate tumors with low levels of PTEN and high levels of HER2/3 have a poor prognosis. This is functionally relevant, as targeting Her2 activation to the murine prostate cooperates with Pten loss and drives CaP progression. Mechanistically, this is associated with activation of the MAPK pathway and abrogation of the Pten loss-induced cellular senescence program. Importantly, inhibition of MEK function strongly suppressed proliferation within these tumors by restoring the Pten loss-induced cellular senescence program. Taken together, these data suggest that stratification of CaP patients for HER2/3 and PTEN status could identify patients with aggressive CaP who may respond favorably to MEK inhibition.