The molecular pathogenesis of prostate cancer: Implications for prostate cancer prevention☆

Abstract 

Prostate cancer has become 1 of the most commonly diagnosed cancers in the United States and 1 of the leading causes of cancer death in North America and Western Europe. Survey studies of prostate tissues obtained at autopsy indicate that the development of life-threatening prostate cancer in the US likely occurs over decades. Insights from epidemiologic studies implicate environmental factors, principally dietary components, as major risk factors for prostate cancer development. An accumulating body of basic research data suggests that normal and neoplastic prostate cells may be subjected to a relentless barrage of genome-damaging stresses, and that dietary components and male sex steroids might modulate the level of genome threatening insults. Finally, over the past 5 years, analyses of somatic genome alterations in prostatic carcinoma cells have revealed that somatic inactivation of GSTP1, encoding the carcinogen-detoxification enzyme glutathione S-transferase π, may serve as an initiating genome lesion for prostatic carcinogenesis. These diverse observations can be integrated into a transcendent mechanistic hypothesis for the pathogenesis of prostate cancer: normal prostate cells acquiring somatic GSTP1 defects may suffer chronic genome damage, influenced by dietary practices, that promote neoplastic transformation, while prostatic carcinoma cells, which characteristically contain defective GSTP1 alleles, remain susceptible to further genome-damaging stresses that promote malignant cancer progression. This hypothesized critical role for GSTP1 inactivation in the earliest steps of prostatic carcinogenesis provides several attractive opportunities for prostate cancer prevention strategies, including (1) restoration of GSTP1 function, (2) compensation for inadequate GSTP1 activity (via use of therapeutic inducers of other glutathione S-transferases (GST), and (3) abrogation or attenuation of genome-damaging stresses.