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 pi, 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.
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