The epidemiology of prostate cancer - with a focus on nonsteroidal anti-inflammatory drugs

Harvard University, Cambridge, Massachusetts, United States
Hematology/Oncology Clinics of North America (Impact Factor: 2.07). 09/2006; 20(4):797-809. DOI: 10.1016/j.hoc.2006.03.002
Source: PubMed

ABSTRACT Aspirin and other NSAIDs have a potential role in the primary and secondary prevention of many common diseases associated with aging, including the top two causes of mortality in the United States-cardiovascular disease and cancer. These agents may be beneficial in the management of Alzheimer's disease,other forms of dementia, and Parkinson's. disease. Because men with prostate cancer or precancer are likely to present with coexisting conditions that would be affected by systemic aspirin, NSAID, or other COX-2 inhibitor therapies, it is important to consider any possible preventive studies or future clinical recommendations of aspirin or NSAIDs for prostate cancer within the context of these comorbid conditions. Aspirin or nonaspirin NSAIDs may be appropriate prevention therapy for patients at high risk of prostate cancer, myocardial infarction, Parkinson's disease, Alzheimer's disease, lung cancer, or colorectal cancer, but low risk for gastrointestinal complications or stroke. Further quantitative comparative studies of the risks and benefits of these common comorbidities in older Americans, with special attention to dose and duration parameters, are warranted.

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    ABSTRACT: Background:Transcription factor EGR3 (Early Growth Response 3) is a little-studied member of the EGR family that is highly expressed in human prostate tumours compared with normal tissue. Its function in prostate cancer, however, is unknown.Methods:Stable shRNA silencing was achieved in naturally overexpressing prostate cancer cells, followed by Affymetrix expression analysis. Fold changes of ⩾2 and ⩽-2 were considered valid and t-tests P-values of ⩽0.01 were considered statistically significant. Potential EGR3 target genes were validated by real-time qPCR, chromatin immunoprecipitation, and gain-of-function experiments. Promoter analysis confirmed the presence of consensus binding sites in the promoters of target genes.Results:Early Growth Response 3 regulates the expression of ∼330 genes, 35% of which are involved in immune responses and inflammatory processes, and 15% crosstalk with the NF-κB signalling pathway. In particular, EGR3 induces the expression of over 50 secreted cytokines, growth factors, and matrix remodelling factors. Two interleukins of great relevance to prostate cancer, IL6 and IL8, were further validated as EGR3 target genes: both promoters contain EGR consensus binding sites and are pulled down in intact cells by EGR3 chromatin immunoprecipitation. Silencing of EGR3 decreased IL6 and IL8 expression, whereas overexpression of EGR3 in nontransformed cells induced IL6 and IL8 expression.Conclusions:Chronic inflammation plays a critical role in prostate cancer and elevated production of pro-inflammatory cytokines IL8 and IL6, in particular, contributes to disease progression and to the onset of castration resistance. It is shown for the first time that EGR3 is involved in the upregulation of both IL6 and IL8. Together with our previous observation that EGR3 is highly expressed in prostate tumours compared with normal tissue and strongly correlates with IL6 and IL8 expression in clinical samples, the present study suggests that EGR3 promotes excessive production of IL6 and IL8 observed during the progression of prostate cancer.British Journal of Cancer advance online publication, 29 January 2015; doi:10.1038/bjc.2014.622
    British Journal of Cancer 01/2015; 112(4). DOI:10.1038/bjc.2014.622 · 4.82 Impact Factor
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    ABSTRACT: The high global incidence of prostate cancer has led to a focus on chemoprevention strategies to reduce the public health impact of the disease. Early studies indicating that selenium and vitamin E might protect against prostate cancer encouraged large-scale studies that produced mixed clinical results. Next-generation prostate cancer prevention trials validated the impact of 5α-reductase inhibitors in hormone-responsive prostate cancer, and these results were confirmed in follow-up studies. Other interventions on the horizon, involving both dietary and pharmacological agents, hold some promise but require further investigation to validate their efficacy. In this Review, we discuss the clinical and preclinical evidence for dietary and pharmacological prevention of prostate cancer and give an overview of future opportunities for chemoprevention.
    Nature Reviews Clinical Oncology 11/2013; DOI:10.1038/nrclinonc.2013.211 · 15.03 Impact Factor
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    ABSTRACT: We discovered that PhIP treatment causes widespread epithelial atrophy in the rat ventral prostate that precedes the development of PIN. This data supports the contention that the PhIP-treated rat model of prostate cancer is a valid model for studying the development of PIA, PIN and early carcinoma. The results raise the novel hypothesis that suggests that the extensive atrophy that is seen in men with prostate cancer, and which has been associated with PIN and prostate cancer, may be caused by ingestion of cooked meats. This result will open up new areas of investigation into this question. For example, it would be highly feasible and reasonable to ask in a pathological-epidemiological study to determine whether the extent of prostate atrophy correlated with dietary intake of PhIP. Also, broccoli and celebrex can decrease mutations in the rat prostate induced by PhIP indicating they may be effective chemopreventative agents. Preliminary analyzes indicates that short term treatment with PhIP (4 weeks) combined with viral infection does not increase PIN or prostate cancer lesions in Fisher Rats suggesting that longer term treatment is necessary. Additional studies to complete this work are ongoing using funding sources outside of the DOD. In addition we have successfully contributed to the further instruction of an outstanding Urologist-In-Training in many aspects of prostate cancer research.