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*1 990 US census.

androgen dependent. As a result, this model has several advantages over currently existing models:

1. Mice develop progressive forms of prostatic epithelial hyperplasia and high-grade PIN as early as 10 weeks and invasive prostate adenocarcinoma around 18 weeks of age.42

2. The pattern of metastatic spread of prostate cancer mimics that of human prostate cancer with common sites of metastases being lymph node, lung, kidney, adrenal gland and bone.

3. The development as well as the progression of prostate cancer can be followed within a relatively short period of 10-30 weeks.

4. Spontaneous prostate tumors arise with 100% frequency.

5. Animals may be screened for the presence of the prostate cancer transgene prior to the onset of clinical prostate cancer.

Another animal model is the transgenic mouse model that contains a probasin promoter that controls the ECO:R1 gene. This gene product has been implicated in the induction of genomic instability.44 Prostates from these animals were followed prospectively from 4 to 24 months of age and showed the progressive presence of mild to severe hyperplasia, low-grade PIN, high-grade PIN and then well-differentiated adenocarcinoma of the prostate.44 Stanbrough etal. (2001) demonstrated that transgenic mice that have prostatic overexpression of androgen receptor (AR) protein develop focal areas of high-grade PIN.45

The mechanism of prostate carcinogenesis appears to be involve estrogenic signaling. Wang etal. (2001) treated wildtype mice with testosterone propionate and estradiol for 4 months.46 These mice developed prostatic hyperplasia, high-grade PIN and invasive prostate cancer. When a-ERKO mice, mice that have the ERa genetically knocked out, are treated the same way, they develop prostatic hyperplasia, but not high-grade PIN or invasive prostate cancer.46 Similarly, a prospective, placebo-controlled study of TRAMP mice treated with an antiestrogen, Acapodene (toremifene), was performed to pharmacologically antagonize ERa. These Acapodene-treated TRAMP mice had a reduction in high-grade PIN, significant decrease in prostate cancer incidence and an increase in animal survival. Thus, estrogenic signally through ERa may play a key role29 in prostate carcinogenesis and that high-grade PIN was observed to be in the direct causal pathway to prostate cancer.

The dog is the only non-human species in which spontaneous prostate cancer occurs and, like humans, the rate of canine prostate cancer increases with aging.47-51 High-grade PIN has been also observed in the prostates of these animals.48-51 Canine high-grade PIN shows cytological features identical to the human counterpart, including cell crowding, loss of polarity, and nuclear and nucleolar enlargement. Like prostatic adenocarcinoma, high-grade PIN also increases with aging.48 Highgrade PIN appears to represent an early event in prostate carcinogenesis that occurs with high frequency within the prostates of pet dogs sharing the same environment as humans. In this model, high-grade PIN was determined to be an intermediate step between benign epithelium and invasive carcinoma. Thus, like the transgenic mouse models, the canine model supports high-grade PIN as part of a continuum in the progression of prostate cancer.

Epidemiologic evidence

A role for high-grade PIN in the development of prostate adenocarcinoma is based on the fact that the prevalence of both high-grade PIN and prostate cancer increases with patient age and that high-grade PIN precedes the onset of prostate cancer by less than one decade.20'34 The severity and frequency of high-grade PIN in prostates with histological cancer is greatly increased (73% of 731 specimens) when compared to prostates without cancer (32% of 876 speci-mens).4,18,52-54 When high-grade PIN is found on needle biopsy, there is a 30-50% risk of finding carcinoma on subsequent biopsies over 3-5 years, and most patients with high-grade PIN develop carcinoma within 10 years.4 One retrospective study revealed that the amount of high-grade PIN for 42 patients followed over 3 years was 12.5% in 1997, 33% in 1998 and 47% in 1999, demonstrating that the volume of highgrade PIN progressively increases over time.

In general, the rate of high-grade PIN appears to be similar for all men across all ages regardless of race and geographical location.4 However, if specific age groups are compared between races, there are significant differences in the frequency of high-grade PIN. African American men have the highest incidence of prostate cancer that is about 50% more than Caucasians.20,31,33,55 Consistent with high-grade PIN being the precursor lesion of prostate cancer, African American men have a greater prevalence of high-grade PIN when compared to Caucasians in the 50-60 year age group, the decade preceding the manifestation of most clinically detected prostate cancers.20,31,33,56 In contrast, Asians have the lowest clinically detected rate of prostate cancer. Several studies from Japan have shown that Japanese men living in Osaka, Japan, have a significantly lower incidence of high-grade PIN compared to men residing in the USA.57,58 Interestingly, those Japanese men diagnosed with high-grade PIN also had an increased likelihood of developing prostate cancer, suggesting that high-grade PIN is a precursor of clinical prostate cancer in

Prostate Cancer: Science and Clinical Practice

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