Statin medication use and the risk of biochemical recurrence after radical prostatectomy

BACKGROUND:

Although controversial, evidence suggests statins may reduce the risk of advanced prostate cancer (PC), and recently statin use was associated with prostate‐specific antigen (PSA) reductions among men without PC. The authors sought to examine the association between statin use and PSA recurrence after radical prostatectomy (RP).

METHODS:

The authors examined 1319 men treated with RP from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Time to PSA recurrence was compared between users and nonusers of statin at surgery using Cox proportional hazards models adjusted for multiple clinical and pathological features.

RESULTS:

In total, 236 (18%) men were taking statins at RP. Median follow‐up was 24 months for statin users and 38 for nonusers. Statin users were older (P < .001) and underwent RP more recently (P < .001). Statin users were diagnosed at lower clinical stages (P = .009) and with lower PSA levels (P = .04). However, statin users tended to have higher biopsy Gleason scores (P = .002). After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence (hazard ratio “HR”, 0.70; 95% confidence interval “CI”, 0.50‐0.97; P = .03), which was dose dependent (relative to no statin use; dose equivalent<simvastatin 20 mg: HR, 1.08; 95% CI, 0.66‐1.73; P = .78; dose equivalent = simvastatin 20 mg: HR, 0.57; 95% CI, 0.32‐1.00; P = .05; dose equivalent>simvastatin 20 mg: HR, 0.50; 95% CI, 0.27‐0.93; P = .03).

CONCLUSIONS:

In this cohort of men undergoing RP, statin use was associated with a dose‐dependent reduction in the risk of biochemical recurrence. If confirmed in other studies, these findings suggest statins may slow PC progression after RP. Cancer 2010. © 2010 American Cancer Society.     

Statin use and prostate cancer risk in a large population-based setting

BACKGROUND: Statins are a commonly used cholesterol-lowering drug, which also have the potential to affect cancer risk and progression. Results from previous studies offer mixed conclusions. METHODS: To evaluate the relation between statin use and prostate cancer risk, we conducted a retrospective cohort study during 1 January 1990 to 31 August 2005 among men 45-79 years receiving care within Group Health, an integrated healthcare delivery system. Information on statin use and covariates were obtained from health plan databases. We identified incident prostate cancer cases through the Surveillance, Epidemiology, and End Results cancer registry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for prostate cancer among statin users compared to non-users. RESULTS: Among 83,372 men studied, median follow-up time was 5.7 years and 2,532 prostate cancer cases were identified. About 14.4% used statins over the study period and median duration of use was 3.3 years. Compared to non-users, hydrophobic statin users had a reduced risk of prostate cancer (HR = 0.79; 95% CI, 0.66-0.94), and results are suggestive of a reduced risk among ever users of statins (HR = 0.88; 95% CI, 0.76-1.02) and hydrophilic statin users (HR = 0.67; 95% CI, 0.33-1.34). There was no trend in risk by duration of statin use, and no association between statin use and cancer aggressiveness, stage, or grade. CONCLUSION: Overall, this study does not support an associated between statin use and prostate cancer but a reduced risk cannot be ruled out.     

Effect of the correction for noncompliance and contamination on the estimated reduction of metastatic prostate cancer within a randomized screening trial (ERSPC section Rotterdam)

The European Randomized study of Screening for Prostate Cancer (ERSPC) has recently reported a 20% reduction in death from prostate cancer in a population‐based prostate cancer screening (core age group: 55–69 years of age). The effect of screening may be diluted by noncompliance in the screening arm and contamination by PSA testing in the control arm. The purpose is to analyze the effect of prostate cancer screening on the incidence of metastatic prostate cancer, both with and without adjustment for noncompliance and contamination. We analyzed the occurrence of metastases in 42,376 men aged 55–75 years who were randomized in the Rotterdam section of the ERSPC between 1993 and 1999. Contamination adjustment was based on follow‐up findings and questionnaire data from all men in the control group who developed prostate cancer and from a random sample of 291 men without cancer who had a PSA test. Prostate cancer screening significantly reduced the occurrence of metastatic prostate cancer in the intention‐to‐screen analysis [RR 0.75, 95% CI 0.59–0.95, p = 0.02] and more so in adjusted analyses; contamination adjusted RR 0.73, 95% CI 0.56–0.96; noncompliance adjusted RR 0.72, 95% CI 0.55–0.95 and fully adjusted analysis RR 0.68, 95% CI 0.49–0.94, p = 0.02. In the population of ERSPC Rotterdam (N = 42,376 men), screening reduces the risk to be diagnosed with metastatic prostate cancer considerably on population level, an effect which is even more pronounced in men who are in fact screened.     

Variation in general practice prostate‐specific antigen testing and prostate cancer outcomes: An ecological study

Knowledge is sparse about the consequences of variation in prostate‐specific antigen (PSA) testing rates in general practice. This study investigated associations between PSA testing and prostate cancer‐ related outcomes in Danish general practice, where screening for prostate cancer is not recommended. National registers were used to divide general practices into four groups based on their adjusted PSA test rate 2004–2009. We analysed associations between PSA test rate and prostate cancer‐related outcomes using Poisson regression adjusted for potential confounders. We included 368 general practices, 303,098 men and 4,199 incident prostate cancers. Men in the highest testing quartile of practices compared to men in the lowest quartile had increased risk of trans‐rectal ultrasound (incidence rate ratio (IRR): 1.20, 95% CI, 0.95–1.51), biopsy (IRR: 1.76, 95% CI, 1.54–2.02), and getting a prostate cancer diagnosis (IRR: 1.37, 95% CI, 1.23–1.52). More were diagnosed with local stage disease (IRR: 1.61, 95% CI, 1.37–1.89) with no differences regarding regional or distant stage. The IRR for prostatectomy was 2.25 (95% CI, 1.72–2.94) and 1.28 (95% CI, 1.02–1.62) for radiotherapy. No differences in prostate cancer or overall mortality were found between the groups. These results show that the highest PSA testing general practices may not reduce prostate cancer mortality but increase the downstream use of diagnostic and surgical procedures with potentially harmful side effects.     

The risk of prostate cancer for men on aspirin,statin or antidiabetic medications

BackgroundA decreased risk of prostate cancer (PCa) has been suggested in men taking aspirin, statins and metformin, although the evidence has been conflicting. We estimated the association between prescribed medications, prostate specific antigen (PSA) levels and the risk of either any PCa or high-grade PCa.MethodsThis population-based cohort study included 185,667 men having a first recorded PSA test and 18,574 men having a first prostate biopsy in Stockholm County, Sweden for the period 2007–2012. Detailed clinical information including PSA levels, biopsy results, comorbidities and educational level were obtained from population-based registers. High-grade prostate cancer was defined as a Gleason score of seven or higher. Differences in PSA levels by medication status were estimated using linear regression on log PSA values. PCa risk was estimated using multivariate logistic regression.ResultsCompared with men who were not on medication, the PSA level at the first PSA test was lower among men using 75 mg/dose aspirin (−3.9% change in PSA concentration; 95% confidence interval (CI): −5.8 to −2.1), statin (−4.6%; 95% CI: −6.2 to −2.9), metformin (−14%; 95% CI: −17 to −12) and insulin (−16%; 95% CI: −18 to −14). Men using any statins had an increased risk of both high-grade PCa (odds ratio (OR) 1.25; 95% CI: 1.10–1.42) and PCa of any grade (OR 1.16; 95% CI 1.04–1.29). There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa.ConclusionWe found no protective effect of aspirin, statins or antidiabetics in terms of risk for any PCa or high-grade PCa. Use of any statins was associated with an elevated risk of being diagnosed with high-grade prostate cancer.     

The Finnish prostate cancer screening trial: Analyses on the screening failures

Prostate cancer (PC) screening with prostate‐specific antigen (PSA) has been shown to decrease PC mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). However, in the Finnish trial, which is the largest component of the ERSPC, no statistically significant mortality reduction was observed. We investigated which had the largest impact on PC deaths in the screening arm: non‐participation, interval cancers or PSA threshold. The screening (SA) and control (CA) arms comprised altogether 80,144 men. Men in the SA were screened at four‐year intervals and referred to biopsy if the PSA concentration was ≥4.0 ng/ml, or 3.0–3.99 ng/ml with a free/total PSA ratio ≤16%. The median follow‐up was 15.0 years. A counterfactual exclusion method was applied to estimate the effect of three subgroups in the SA: the non‐participants, the screen‐negative men with PSA ≥3.0 ng/ml and a subsequent PC diagnosis, and the men with interval PCs. The absolute risk of PC death was 0.76% in the SA and 0.85% in the CA; the observed hazard ratio (HR) was 0.89 (95% confidence interval (CI) 0.76–1.04). After correcting for non‐attendance, the HR was 0.78 (0.64–0.96); predicted effect for a hypothetical PSA threshold of 3.0 ng/ml the HR was 0.88 (0.74–1.04) and after eliminating the effect of interval cancers the HR was 0.88 (0.74–1.04). Non‐participating men in the SA had a high risk of PC death and a large impact on PC mortality. A hypothetical lower PSA threshold and elimination of interval cancers would have had a less pronounced effect on the screening impact.     

Body mass index in relation to serum prostate‐specific antigen levels and prostate cancer risk

High Body mass index (BMI) has been directly associated with risk of aggressive or fatal prostate cancer. One possible explanation may be an effect of BMI on serum levels of prostate‐specific antigen (PSA). To study the association between BMI and serum PSA as well as prostate cancer risk, a large cohort of men without prostate cancer at baseline was followed prospectively for prostate cancer diagnoses until 2015. Serum PSA and BMI were assessed among 15,827 men at baseline in 2010–2012. During follow‐up, 735 men were diagnosed with prostate cancer with 282 (38.4%) classified as high‐grade cancers. Multivariable linear regression models and natural cubic linear regression splines were fitted for analyses of BMI and log‐PSA. For risk analysis, Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) and natural cubic Cox regression splines producing standardized cancer‐free probabilities were fitted. Results showed that baseline Serum PSA decreased by 1.6% (95% CI: ?2.1 to ?1.1) with every one unit increase in BMI. Statistically significant decreases of 3.7, 11.7 and 32.3% were seen for increasing BMI‐categories of 25 < 30, 30 < 35 and ≥35 kg/m², respectively, compared to the reference (18.5 < 25 kg/m²). No statistically significant associations were seen between BMI and prostate cancer risk although results were indicative of a positive association to incidence rates of high‐grade disease and an inverse association to incidence of low‐grade disease. However, findings regarding risk are limited by the short follow‐up time. In conclusion, BMI was inversely associated to PSA‐levels. BMI should be taken into consideration when referring men to a prostate biopsy based on serum PSA‐levels.     

Snus use,smoking and survival among prostate cancer patients

Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (i) never users of any tobacco, (ii) exclusive snus: ever users of snus only, (iii) exclusive smokers: ever smokers (cigarette, cigar and/or pipe) only and (iv) ever users of both snus and smoking. Hazard ratios for prostate cancer‐specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis and body mass index at baseline. During 36 years of follow‐up, 4,758 patients died—2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05–1.27) and total mortality (HR 1.17, 95% CI: 1.09–1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03–1.49) and total mortality (HR 1.19, 95% CI: 1.04–1.37). Among men diagnosed with nonmetastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66–6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco‐related components such as nicotine or tobacco‐specific carcinogens may promote cancer progression independent of tobacco's combustion products.     

Prospective study of Type 2 diabetes mellitus,anti‐diabetic drugs and risk of prostate cancer

Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti‐diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82–0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77–1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55–0.98), compared to men with T2DM not on anti‐diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95–1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.     

The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate‐specific Antigen‐era

Widespread prostate‐specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70–79, tumor was found in 36% of Caucasians and 51% of African‐Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well‐recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow‐up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.     

A 24‐year prospective study of dietary α‐linolenic acid and lethal prostate cancer

Several meta‐analyses have attempted to determine the relationships between intake of α‐linolenic acid (ALA) and prostate cancer, but results were inconclusive. 47,885 men aged 40–75 years without prior cancer in the Health Professionals Follow‐Up Study were prospectively followed from 1986 to 2010. Intake of ALA was determined from validated food frequency questionnaires every 4 years. We used multivariate Cox proportional hazards models to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for lethal prostate cancer (distant metastasis or prostate cancer death). 386 lethal prostate cancers were diagnosed in the pre‐PSA era (before February, 1994) and 403 cancers in the PSA era. Intake of ALA was associated with increased risk of lethal prostate cancer in the pre‐PSA era (comparing top to bottom quintile of intake, multivariate‐adjusted HR = 1.78; 95% CI = 1.22–2.06; p_trend = 0.003), but not in the PSA era (HR = 0.81; 95% CI = 0.56–1.17; p_trend = 0.53), and the difference in associations was statistically significant (p for interaction = 0.02). Mayonnaise, a primary food source of ALA intake in our cohort, was likewise only significantly associated with lethal prostate cancer in the pre‐PSA era. Among many other fatty acids that are correlated with ALA due to shared food sources, none was associated with lethal prostate cancer in the pre‐PSA era. In conclusion, higher intake of ALA was associated with an increased risk of lethal prostate cancer in the pre‐PSA era, but not in the PSA era. Potential reasons for the differential associations warrant further investigation.     

Dairy intake in relation to prostate cancer survival

Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer‐specific mortality with increased high‐fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989–1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer‐specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer‐specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high‐fat milk intake was not associated with prostate cancer‐specific death (95% CI: 0.78, 2.10; p‐trend = 0.32; multivariate‐adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high‐fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p‐trend = 0.004; multivariate‐adjusted model). Low‐fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high‐fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high‐fat milk intake may promote prostate cancer progression.     

Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: The Japan Public Health Center‐based prospective study

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center‐based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40–69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow‐up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ‐localized and 30 were of an undetermined stage. Alcohol consumption was dose‐dependently associated with advanced prostate cancer [nondrinkers: reference, 0–150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83–1.82; 150–300 g/week: HR = 1.51, 95% CI = 1.04–2.19; ≥300 g/week: HR = 1.41, 95% CI = 0.97–2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer.     

Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta‐analysis

Statins have shown antineoplastic properties in preclinical studies with breast cancer cells. They inhibit the enzyme “HMG CoA reductase” and the expression of this enzyme in cancer cells has been implicated as a favorable prognostic factor in patients with breast cancer. After a search of MEDLINE and Embase from inception through November 2015, 817 abstracts were reviewed to identify studies that described an association between statin use and outcomes in breast cancer. A total of 14 studies which included 75,684 women were identified. In a meta‐analysis of 10 studies, statin use was associated with improved recurrence‐free survival (RFS; HR 0.64; 95% CI 0.53–0.79, I² = 44%). Furthermore, this RFS benefit appeared to be confined to use of lipophilic statins (HR 0.72; 95% CI 0.59–0.89) as hydrophilic statin use was not associated with improvement in RFS (HR 0.80; 95% CI 0.44–1.46). Statin users similarly showed improved overall survival in a meta‐analysis with substantial heterogeneity (8 studies, HR 0.66; 95% CI 0.44–0.99, I² = 89%). Statin users also had improved cancer‐specific survival, although this relationship was measured with less precision (six studies, HR 0.70; 95% CI 0.46–1.06, I² = 86%). In conclusion, breast cancer patients who use statins, or specifically, lipophilic statins show improved recurrence‐free survival. Statin users also had improved overall survival and cancer‐specific survival. These findings should be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs should be identified.     

High Receipt of Statins Reduces the Risk of Lung Cancer in Current Smokers With Hypercholesterolemia: The National Health Insurance Service–Health Screening Cohort

BackgroundThe incidence and mortality of lung cancer have risen steadily with the increasing popularity of tobacco smoking. Observational studies suggest that statins, which are widely used to lower cholesterol, may prevent lung cancer; however, other studies have produced conflicting results. We investigated the effect of statin receipt on lung cancer risk in Korean men according to smoking status.Patients and MethodsWe collected data from the 2002-2015 National Health Insurance Service–National Health Screening Cohort (NHIS-HEALS). We included a total of 16,588 men in the final analysis. We classified the participants as having high or low statin receipt or as not receiving statins. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer risk by statin receipt after adjusting for potential confounders.ResultsWe identified 363 patients with a new diagnosis of lung cancer from 2005 to 2015. Compared to participants who did not receive statins, high statin receipt resulted in a reduced lung cancer risk (HR = 0.64; 95% CI, 0.47, 0.85) after adjustment for confounders. Among current smokers, the fully adjusted HR for high statin receipt compared to those who did not receive statin therapy was 0.50 (95% CI, 0.32, 0.79).ConclusionHigh statin receipt was associated with lower risk of lung cancer in Korean men with hypercholesterolemia, especially current smokers.     

Association between plasma cholesterol and prostate cancer in the PSA era

We previously found that statin users had a lower risk of advanced and possibly high-grade prostate cancer compared with nonusers. We hypothesize that statins' effects on cholesterol synthesis may explain those findings because prostate cancer cells exhibit cholesterol dysregulation. Thus, we investigated whether low plasma cholesterol is associated with prostate cancer overall and by stage and grade. Participants were drawn from the 18,018 members of the Health Professionals Follow-Up Study who provided blood in 1993-1995. We ascertained 698 incident cases through January 2000. Controls were 698 men who had a PSA test and were matched to cases. Plasma cholesterol was measured enzymatically. Conditional logistic regression was used to estimate multivariable ORs and 95% CIs of total, clinically organ-confined (n = 518), advanced (T3b or worse; n = 61), low-grade (Gleason sum < 7; n = 386) and high-grade (Gleason sum > or = 7, n = 247) disease. Low cholesterol (<25th percentile vs. > or =25th percentile) was not associated with total (OR = 0.93, 95% CI: 0.72-1.20), organ-confined (OR = 0.87, 95% CI: 0.64-1.18) or low-grade (OR = 1.06, 95% CI: 0.75-1.51) disease. However, men with low cholesterol had a lower risk of high-grade disease (OR = 0.61, 95% CI: 0.39-0.98), especially if organ-confined (OR = 0.54, 95% CI: 0.29-0.99). The association for advanced disease appeared inverse, but number of cases was small (OR = 0.42, 95% CI: 0.13-1.36). Associations remained after excluding cholesterol-lowering drug users. These results coupled with prior statin findings suggest that mechanistic studies on cholesterol metabolism should be pursued to understand a possible target for preventing poorly differentiated prostate cancers.