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

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 factor s for prostate cancer development. An accumulating body of basic research d ata suggests that normal and neoplastic prostate cells may be subjected to a relentless barrage of genome-damaging stresses, and that dietary componen ts and male sex steroids might modulate the level of genome threatening ins ults. Finally, over the past 5 years, analyses of somatic genome alteration s in prostatic carcinoma cells have revealed that somatic inactivation of G STP1, encoding the carcinogen-detoxification enzyme glutathione S-transfera se pi, may serve as an initiating genome lesion for prostatic carcinogenesi s. These diverse observations can be integrated into a transcendent mechani stic hypothesis for the pathogenesis of prostate cancer: normal prostate ce lls acquiring somatic GSTP1 defects may suffer chronic genome damage, influ enced by dietary practices, that promote neoplastic transformation, while p rostatic carcinoma cells, which characteristically contain defective GSTP1 alleles, remain susceptible to further genome-damaging stresses that promot e malignant cancer progression. This hypothesized critical role for GSTP1 i nactivation in the earliest steps of prostatic carcinogenesis provides seve ral attractive opportunities for prostate cancer prevention strategies, inc luding (1) restoration of GSTP1 function, (2) compensation for inadequate G STP1 activity (via use of therapeutic inducers of other glutathione S-trans ferases (GST), and (3) abrogation or attenuation of genome-damaging stresse s. (C) 2001, Elsevier Science Inc.