Androgens in Health and Disease.pdf - E Library

Chapter 9/Androgen Signaling in Prostatic Neoplasia and Hyperplasia 161
Although loss of coactivator interactions may lead to a reduction in activity, there is
evidence from transient transfection studies indicating that some coactivators may
broaden the ligand specificity of AR. Studies from the Chang laboratory indicate that
ARA70 cotransfected with AR in DU145 prostate cancer cells that are AR negative
causes estradiol and some of the AR antagonists to act as agonists (46). In addition, a
recent report has shown that the majority of recurrent prostate cancers express high
levels of the androgen receptor and two nuclear receptor coactivators, transcriptional
intermediary factor 2 and steroid receptor coactivator 1. Overexpression of these
coactivators increases AR transactivation at physiological concentrations of adrenal
androgen, thus providing a mechanism for AR-mediated prostate cancer recurrence (47).
Collectively, these studies suggest that coactivators play a critical role in normal AR
function. Abnormalities in coactivator structure or in regions of AR that interact with
coactivators will have profound effects on androgen action.
PROSTATE CANCER
Epidemiology
The prevalence of prostate cancer at autopsy is considerably higher than its clinical
incidence. The epidemiology of prostate cancer is complicated by histological evidence
that the prevalence of prostate cancer at autopsy (latent prostate cancer) increases progressively
in aging men. It occurs in 15–20% of men 40–50 yr of age and in >50% of men
60–70 yr of age (48,49). The factors responsible for causing a latent prostate cancer to
become a clinical prostate cancer are poorly understood.
The clinical incidence of prostate cancer varies greatly, dependent on ethnic background
and country of residence. In the United States, it has been estimated that approx
75% of prostate cancers (the occult prostate cancers) will never become diagnosed (50).
There is more than a 10-fold difference in the incidence rates of clinical prostate cancer
in different countries. This is in sharp contrast with the prevalence of latent prostate
cancer, which is roughly the same worldwide (51). Epidemiological observations suggest
that diet, genetic susceptibility, environmental carcinogens, and endocrine function
may influence the development of prostate cancer. The fact that Japanese and Chinese
males immigrating to the United States experience a sharp increase in prostate cancer
prevalence in the first and second generation indicates the importance of environmental
factors (52). Notably, data on diet and prostate cancer have revealed a strong correlation
between per capita fat intake and prostate cancer incidence and mortality (53). Thus,
significant ethnic differences in the incidence of clinical prostate cancer seem to provide
opportunities for learning more about the pathogenesis of this disease. Potential differences
in sex steroid levels have been the focus for many studies.
The incidence and mortality rates from prostate cancer vary among different ethnic
groups in the United States. They are higher in African-American (224 and 55/100,000
persons/yr), intermediate among white (150 and 24/100,000), and lowest among Asian-
American (82 and 10/100,000) (1). Therefore, investigators have evaluated African-
Americans, European-Americans, Asian-Americans, and Asians living in Asia.
Correlation Between Prostate Cancer Epidemiology
and Serum Hormonal Levels
Serum hormone levels at the time when prostate cancer is diagnosed may not be
representative of those that occur during the development of prostate cancer, so inves-