Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer

Abstract

Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms. Experimental Design: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue. Results: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60–0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19–0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95–1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103). Conclusions: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.

MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer

“…In the present study, we attempted to use the FDA-approved drugs Simvastatin and Verteporfin to achieve pharmacological inhibition of key nodes in the MYBL2/RACGAP1/RhoA/YAP signaling cascade and found that these treatment regimens were sufficient to reverse ADT resistance and the metastatic phenotype in CRPC cells. Consistent with our results, growing evidence supports the role of statins in reducing the risk of advanced and lethal PCa 60 . Further clinical trials have shown that statins are promising candidates for adjuvant therapy with abiraterone in patients with metastatic CRPC and correlated with superior overall survival 61 .…”

Statins: a repurposed drug to fight cancer

“…Another analysis of 1,001 prostate cancer patients (289 statin users) reported a 0.19 hazard ratio for prostate cancer-specific death among statin users compared with men who did not use statins (95% CI, 0.06–0.56) [ 66 ]. A recent clinical study showed that statin use is associated with a reduced risk of phosphatase and tensin homolog (PTEN)-negative and fatal prostate cancer [ 23 ]. However, the results of a population-based epidemiologic study showed that the use of statins was not associated with overall prostate cancer risk [ 67 ], although the credibility of the results of the study are open to question due to the relatively small sample size and the existence of potential selection and recall biases.…”

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

“…The Pten-null senescent PCa tumors from mice had high infiltration of MDSCs in the TME promoted by activation of the Janus kinase (JAK)2/STAT3 pathway and secretion of chemoattractant molecules to the TME [57,58]. A recent populationbased study of >6000 PCa related PTEN loss to the statin pathway and inflammation and immune activation in lethal PCa [66]. These findings are supported by a new study of Pten knockout mice, which used methylation and transcriptomic profiling to show that loss of PTEN drives global changes in DNA CpG methylation with associated gene expression changes, thus affecting several inflammatory and immune molecular pathways during PCa development [65].…”