Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification

Mechanisms of prostate cancer recurrence during androgen deprivation are poorly understood. We recently described androgen receptor (AR) gene amplification in 28% of recurrent prostate carcinomas from hormone-refractory prostate cancer patients. To investigate the hypothesis that amplification of the AR gene promotes the growth of hormone-refractory prostate carcinomas, DNA flow cytometric (FCM) studies were carried out to compare matched, primary and hormone-refractory recurrent samples from 31 prostate cancer patients. Recurrent tumours had a higher (P=0.05) S-phase fraction (SPF) (10.6+/-4.6) than corresponding primary tumours from the same patients (7.0+/-4.1) and the frequency of aneuploidy also increased from 8-55%. Recurrent tumours with AR gene amplification had a significantly higher (P=0.02) SPF (14.0+/-6.5) than those with no amplification (9.0+/-2.9). The results suggest that clinical progression of prostate cancer during androgen withdrawal therapy is often associated with increased cell proliferation rate and formation of DNA aneuploidy. AR amplification may be an important molecular mechanism underlying the increase in proliferation rate of some recurrent tumours.     

Mutation screening of the androgen receptor promoter and untranslated regions in prostate cancer

BACKGROUND: Mechanisms, other than gene amplification, leading to overexpression of AR in androgen ablation-resistant prostate cancer remain unknown and could include genetic alterations in the promoter or untranslated regions (UTR) of the AR gene. MATERIALS AND METHODS: DNAs from five prostate cancer cell lines, 19 LuCaP xenografts, 44 clinical tumors, and 36 non-malignant controls were used for screening mutations in the upstream regulatory region, promoter and the 5'- and 3'-UTRs of the AR gene with denaturating high performance liquid chromatography (DHPLC) and sequencing. RESULTS: Ten different sequence variations were found in prostate cancer cell lines and xenografts. However, none of them were recurrent or were found in clinical prostate cancer specimens or in normal controls. CONCLUSIONS: Recurrent mutations in the promoter or UTRs of AR seem to be rare, and thus not likely mechanisms for the increased expression of the gene in the androgen ablation-resistant prostate cancer.     

Gain of androgen receptor gene copies in primary prostate cancer due to X chromosome polysomy

BACKGROUND: Prostate cancer is an androgen dependent tumor. In advanced prostate cancers androgen deprivation has proved to be an effective therapy, but 25% show no response. In this study prostatectomy specimens from patients without preoperative therapy were analyzed to determine the possible mechanism of primary antiandrogen resistance. METHODS: The number of androgen receptor (AR) gene copies and X-centromeres were investigated from 80 prostate cancer specimens by FISH analysis. RESULTS: In 9 out of 80 prostate cancers additional X-chromosomes with the corresponding AR gene could be detected. Polysomy of the X-chromosome correlates with pathological classification and tumor volume. CONCLUSIONS: Additional AR genes due to polysomy of the X-chromosome are present in a subgroup of primary prostate cancers prior to antiandrogen therapy. Because the growth of prostate cancers is androgen dependent, these specimens may have an advantage in low concentrations of androgens. This may be a factor for initial antiandrogen resistance.     

Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients

BACKGROUND: Oncogene amplification and chromosomal anomalies are found in many solid tumors and are often associated with aggressiveness of cancer. We evaluated the frequency and the association of c-myc and androgen receptor (AR) gene amplification and gain of chromosome 8 or X in prostate cancer in Japanese patients. METHODS: We examined a total of 42 prostate cancer specimens, using fluorescence in situ hybridization (FISH). Dual-labeling hybridization with a directly labeled centromere probe for chromosome 8 or X together with a probe for the c-myc or AR locus was performed. RESULTS: Gain of chromosome 8 was identified in 54.8% of specimens and was associated with Gleason sum and nuclear anaplasia in untreated prostate cancers. c-myc gene amplification was found in 14.3% of specimens. Gain of chromosome X was identified in 42.9% of specimens. AR gene amplification was detected in 0 of 37 untreated prostate cancers, but in 1 of 5 hormone-refractory prostate cancers. CONCLUSIONS: Our results suggest that c-myc and AR gene amplification and gain of chromosome 8 or X may be associated with the development and progression of prostate cancers. These results obtained in Japanese cases are consistent with the results observed in prostate cancer in Western countries.     

Racial differences in androgen receptor protein expression in men with clinically localized prostate cancer

PURPOSE: Black American men experience disproportionate mortality from prostate cancer (CaP) compared with white American men. Differences in outcome may stem from differences within the androgen axis. Since serum testosterone levels appear to be similar by race in men with CaP, we measured and compared androgen receptor (AR) protein expression in malignant and benign prostate tissue from black and white men who underwent radical prostatectomy for clinically localized CaP. MATERIALS AND METHODS: Archived radical prostatectomy specimens obtained from 25 white and 25 black men had AR protein antigen retrieved and immunostained. AR protein expression from CaP and benign tissue was assessed by 2 methods. Automated digital color video image analysis was used to measure the percent area immunostained for AR protein and the intensity of expression (mean optical density). Visual scoring was performed to compare results with automated values. RESULTS: In black compared with white men malignant nuclei were 27% more likely to immunostain for AR (p = 0.005) and in immunopositive nuclei AR protein expression was 81% greater (p = 0.002). Visual scoring of malignant nuclei revealed that AR immunostaining was significantly increased in black vs white men (171 +/- 40 vs 149 +/- 37, p = 0.048). In immunopositive benign nuclei AR protein expression was 22% greater in black than in white men (p = 0.027). Visual scoring of benign nuclei revealed 20% increased immunostaining in black vs white men, although this difference did not attain statistical significance (p = 0.065). Racial differences in AR protein expression were not explained by age, pathological grade or stage, although serum prostate specific antigen levels were higher in black men (9.7 +/- 7.5 vs 15.5 +/- 12.2 ng/ml, p = 0.049). CONCLUSIONS: AR protein expression was 22% higher in the benign prostate and 81% higher in the CaP of black African compared with white men. CaP may occur at a younger age and progress more rapidly in black than in white men due to racial differences in androgenic stimulation of the prostate.     

RACE AS AN INDEPENDENT PREDICTOR OF OUTCOME AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER

PURPOSE: We analyze the outcome after prostatectomy or radiotherapy for localized prostate cancer with respect to race. MATERIALS AND METHODS: A total of 2,219 consecutive patients with prostate cancer were treated with radiotherapy (1,183) or radical prostatectomy (1,036) between June 1986 and June 1998. Initial prostate specific antigen (PSA) and biopsy Gleason scores were available in all cases. Androgen deprivation was used in 22% of men (492). Of the patients 86% (1,901) were white, including Hispanic and Asian, and 14% (318) were black. The outcomes of interest were biochemical relapse-free survival, clinical relapse-free survival and overall survival. Median followup was 24 months (range 2 to 140). RESULTS: There was no difference in the incidence of familial prostate cancer, patient age at presentation, clinical stage or biopsy Gleason scores between black and white men. However, black men had higher initial PSA levels (median 13.3 versus 8.6 for white men, p<0.001). The 5-year biochemical relapse-free survival rate was 59% for the entire group, 54% (95% confidence interval 44 to 63) for black men and 61% (95% confidence interval 57 to 65) for white men (p = 0.11). Multivariate analysis was performed for the variables of age, race, family history of prostate cancer (brother or father), initial PSA, biopsy Gleason sum, clinical T stage, treatment modality and androgen deprivation. Familial prostate cancer (p = 0.001), higher T stage (p<0.001), higher initial PSA (p<0.001), higher biopsy Gleason score (p<0.001) and use of androgen deprivation (p = 0.001) were independent predictors of biochemical failure and all other factors, including race, were not (p = 0.46). The projected 10-year clinical relapse-free survival rate was 74% for the entire group, and was identical for black and white men (p = 0.77). The projected 10-year overall survival rate for black and white men was 92 and 79%, respectively (p = 0.62). CONCLUSIONS: We have demonstrated a statistically nonsignificant trend for higher biochemical failure rates in black men presenting with localized prostate cancer. This trend could be due to the higher pretreatment PSA levels in black patients. Treatment recommendations should not differ with respect to race.     

Links between genetic and environmental factors and prostate cancer risk.

BACKGROUND: Genetic polymorphisms and expression of steroid receptors may explain why some individuals are more at risk of developing prostate cancer. Some risk factors often discussed are androgen stimulation, and vitamin A and D deficiency. Long CAG-repeats in exon 1 of the androgen receptor (AR) gene on the X chromosome seem to have a protective role against androgen overstimulation. Likewise, long vitamin D receptor alleles in the poly-A tract may prevent vitamin D stimulation. METHODS: Blood samples from 59 Swedish patients with sporadic prostate cancers, 59 with hereditary prostate cancer, and 34 Japanese prostate cancer patients were compared with benign controls. Tissue specimens from 37 Swedish and 23 Japanese prostate cancer patients with matching blood samples were investigated by immunohistochemical techniques. RESULTS: The number of CAG-repeats was identical in sporadic and hereditary prostate cancer patients, but the repeats were significantly shorter than in benign controls. Benign Japanese controls were similar to Swedish controls, but Japanese prostate cancers had longer repeats than did controls. Both the vitamin D and A receptor staining was stronger in Japanese than in Swedish prostate cancer specimens. Prostate cancer occurs approximately 5 years later in Japanese compared with Swedish men. CONCLUSIONS: Varying lengths of CAG-repeats of the androgen receptor cannot fully explain racial differences in clinical prostate cancer incidence. A larger content of vitamin A and D receptors may be linked to a delayed onset of clinical prostate cancer in Japanese men.     

The impact of prior radical prostatectomy in men with metastatic castration recurrent prostate cancer: a pooled analysis of 9 Cancer and Leukemia Group B Trials

PURPOSE: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy. MATERIALS AND METHODS: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes. RESULTS: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9-16.7) and 14.5 months (95% CI 13.5-15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90-1.19, p = 0.65) in men with vs without prostatectomy. CONCLUSIONS: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer.     

Tissue prostate-specific antigen and androgen receptor immunoreactivity in prostate cancer biopsies before, during and after neo-adjuvant androgen deprivation followed by radiotherapy.

OBJECTIVE: The purpose of the study was to examine the immunohistochemical stainability of prostate-specific antigen (PSA) and androgen receptor (AR) in biopsies from localised prostate cancers before treatment, after androgen deprivation and after radiation therapy. PATIENTS AND METHODS: Biopsies were taken from 16 men with prostate cancer (T1-3,Nx,M0) before the start (START) of androgen deprivation with LHRH analogue, during the following pelvic lymph node dissection (PLND), and twice after radiotherapy (POSTRAD and FINAL). RESULTS: Malignant cells were observed in all START, PLND and POSTRAD biopsies and in 6 of 7 FINAL specimens. During androgen suppression and subsequent radiotherapy a gradual reduction in tissue immunoreactivity for PSA and AR was observed paralleled by a reduction in serum PSA. The most striking observation was the complete lack of AR stainability after combined LHRH/radiation therapy. Of the 7 patients who had a long-term follow-up after radiotherapy, 1 patient was cancer negative on biopsy and without AR and PSA stainability. Six patients with cancer-positive FINAL biopsies had regained AR stainability. Five of these latter biopsies also stained for PSA. Five of the six patients had no elevation in serum PSA. CONCLUSION: After combined hormone/radiotherapy serum PSA is a relatively unreliable marker for the demonstration of residual cancer. This combination therapy leads to transient loss of immunohistochemically stained tissue PSA and AR in the residual cancer.     

R726L androgen receptor mutation is uncommon in prostate cancer families in the united states

BACKGROUND: A mutation in the androgen receptor (AR) gene, namely AR R726L, was described in 2% of Finnish men with sporadic or familial prostate cancer and was associated with an approximately sixfold increased risk of prostate cancer. We set out to determine the incidence of this mutation in a sample of men with either early-onset and/or familial prostate cancer in the United States. METHODS: Five hundred forty-eight men with prostate cancer from 411 unrelated families participating in the University of Michigan Prostate Cancer Genetics Project (PCGP) were studied. Allele-specific oligonucleotide hybridization was used to detect the presence of the AR R726L mutation in germline DNA. RESULTS: None of the 548 prostate cancer patients studied, including 513 White, 29 African American, 3 Asian, and 3 Hispanic men, were found to carry the AR R726L allele. Therefore, the prevalence of this allele is significantly less than that observed among Finnish men with prostate cancer (Fisher's exact test, P = 0.002). CONCLUSIONS: The AR R726L allele does not account for a significant proportion of early-onset and/or familial prostate cancer in the United States.     

Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies.     

Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5α‐reductase

OBJECTIVE

The inhibition of 5α‐reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition.

METHODS

We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies.

RESULTS

5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen‐deprivation therapy, and is generally well tolerated.

CONCLUSIONS

Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.     

Associations of serum testosterone with microvessel density,androgen receptor density and androgen receptor gene polymorphism in prostate cancer

PURPOSE: We investigate potential associations of serum testosterone with microvessel density, androgen receptor expression and AR gene polymorphism in men with untreated prostate cancer. MATERIAL AND METHODS: Serum luteinizing hormone, follicle-stimulating hormone, estradiol and testosterone were determined in men with newly diagnosed prostate cancer. The number of tumor vessels per 0.46 mm. and androgen receptor density (as the percent positive nuclei) were quantified immunohistochemically on prostate cancer areas of prostate biopsy specimens. Polymorphisms within the AR gene (number of CAG repeats) were determined by polymerase chain reaction and restriction fragment length polymorphism analysis using DNA from peripheral blood. RESULTS: The 39 men entered into this study were grouped into 16 with low (3 ng./ml. or less, group 1) and 23 with normal (greater than 3 ng./ml., group 2) serum testosterone. Mean prostate specific antigen +/- SD was significantly lower in group 1 than in group 2 (18.8 +/- 11.1 versus 27.2 +/- 12.2 ng./ml., p = 0.03). Mean Gleason score (7.4 +/- 1.3 versus 6.0 +/- 1.2, p = 0.01), androgen receptor density (96.6% +/- 2.8% versus 84.8% +/- 7.2%, p = 0.03) and tumor vessel density (63.0 +/- 30.8/0.46 versus 39.0 +/- 22.9/0.46 mm.2, p = 0.007) were significantly higher in group 1 than in group 2. The number of CAG repeats within the AR gene did not correlation with serum androgen. CONCLUSIONS: Low serum testosterone in men with newly diagnosed prostate cancer is associated with higher tumor microvessel and androgen receptor density as well as with higher Gleason score, suggesting enhanced malignant potential.     

Androgen receptor mutants detected in recurrent prostate cancer exhibit diverse functional characteristics

BACKGROUND: Alterations in the function of androgen receptor (AR) and its signaling pathway may be responsible for the progression of prostate cancer. The goal of the present study was to investigate the potential roles of AR structural and functional alterations in the progression of prostate cancer, and the relationship between the structure and function of the AR. METHODS: AR gene in 58 prostate cancer samples was examined for mutations using PCR-single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Effects of mutations on the structure and function of AR were investigated by androgen-binding assays and transactivation assays, respectively. RESULTS: Four novel somatic mutations (G142V, D221H, E872Q, and M886I) were identified from recurrent prostate cancer samples. None of the AR mutants differed from wild-type AR (wtAR) in their abilities to bind the synthetic androgen methyltrienolone. However, these mutated AR exhibited diverse functional characteristics as compared with wtAR. G142V and D221H showed increased responses to DHT. E872Q could be abnormally activated by 17beta-estradiol, progesterone, and cyproterone acetate (CPA). Furthermore, E872Q and M886I presented increased responses to DHT in the presence of coactivators TIF-2 and CBP, but not p300. On the other hand, although overexpression of corepressors N-CoR and SMRT could result in evident inhibition on DHT- or CPA-induced transactivity of wtAR and the AR mutants, N-CoR displayed stronger inhibitory effects on DHT-induced transactivity of the AR mutants (especially for E872Q and M886I) than that of wtAR. To our knowledge, this is the first characterization of enhanced inhibitory effects of corepressors on the transactivity of the AR mutants found in prostate cancer. CONCLUSIONS: The data presented here demonstrate that AR mutants found in prostate cancer had different functional alterations, which might play an important role in the progression of prostate cancer.     

Hormone-resistant prostate cancer with symptomatic pelvic tumours: patient survival and prognostic factors

OBJECTIVES: To determine the survival and investigate the prognostic significance of immunohistochemical variables and clinical factors in patients with hormone-resistant prostate cancer (HRPC) and symptomatic pelvic tumours, in whom preliminary observations indicated that survival exceeded the median 8-10 months of patients with HRPC and painful bone metastases. PATIENTS AND METHODS: Seventy-five patients with HRPC referred for palliative pelvic radiotherapy between 1980 and 1996 were identified. For all patients at least two prostate biopsies had been obtained, one before primary hormone treatment and at least one after clinical progression despite androgen deprivation (HRPC biopsy). Bone scans at the time of referral were assessed. The medical records were reviewed for clinical variables of possible prognostic significance. Histological grade was recorded, and prostate-specific antigen (PSA), androgen receptors (ARs), Ki-67 and p53 determined immunohistochemically. In 18 HRPC specimens the degree of AR amplification was analysed. RESULTS: Positive staining for ARs was high in the HRPC biopsies, although there was no association with AR amplification. Ki-67 positivity increased after the development of HRPC. The median (range) survival was 14 (1-141) months; age < 65 years was associated with increased survival. In a multivariate analysis the following variables remained independent prognostic factors for survival from the time of the HRPC biopsy: bone metastases (0-10 vs > 10 lesions, P < 0.001), low Ki-67 score (0 vs 1-3, P = 0.006) and low p53 positivity score (0 vs 1-3, P = 0.014) in the HRPC biopsy. CONCLUSIONS: The median survival of patients with HRPC and pelvic tumours requiring palliation seems to exceed that of patients with HRPC and dominating painful bone metastases by at least 4-6 months. Simple clinical (bone metastases) and immunohistochemical variables (Ki-67, p53) enable patients with particularly long survival times to be identified, and in whom palliative treatment needs to be improved.     

Amplification of the androgen receptor may not explain the development of androgen-independent prostate cancer.

OBJECTIVE: To examine the role of androgen receptor (AR) gene amplification and aneusomy of the X chromosome in the development of antiandrogen-resistant prostate cancer. PATIENTS AND METHODS: Twenty patients with prostate cancer resistant to androgen-deprivation therapy were selected for study. The records of patients with tumours before and after antiandrogen therapy, and with a full clinical follow-up, were retrieved. AR gene amplification and X chromosome copy number were assessed by fluorescence in situ hybridization using a labelled probe at locus Xq11-13 for the AR gene and a labelled alpha-satellite probe for the X chromosome. At least 20 nuclei were scored over three tumour areas by two independent observers. RESULTS: Aneusomy of the X chromosome was reported respectively in seven (35%) and 11 (55%) tumours before and after hormone relapse, the AR gene copy number was increased in seven (35%) and 13 (65%), respectively, and AR gene amplification was detected in one (5%) and three (15%), respectively. Neither increased AR copy number nor AR amplification in primary tumours precluded a biological response to androgen-deprivation therapy. CONCLUSION: The rate of AR gene amplification is too low to be solely responsible for the development of antiandrogen-resistant prostate cancer. Also, the presence of amplified AR and cells aneusomic for the X chromosome in primary tumours that respond to androgen-deprivation therapy suggests that an increase in AR gene copy number does not prevent a tumour from responding to this therapy. Therefore other mechanisms which could cause hormone-refractory prostate cancer must be investigated before it is understood why so many patients relapse with this disease.     

Expression and somatic mutation on androgen receptor gene in prostate cancer

BACKGROUND: Lack of androgen receptor (AR) expression or mutation on the AR gene creates the tendency for androgen independence and progression of prostate cancer. However, the association between the progression and AR expression or mutations is still controversial. In this study, we evaluated the prognostic significance of AR expression and mutations in prostate cancers. METHODS: Forty-two prostate adenocarcinomas and three lymph node metastatic lesions sampled prior to hormonal therapy were included in this study; AR expression was analyzed immunohistochemically using an antibody against AR and the result was scored as the percentage of AR-positive tumor cells in the total tumor cells. Polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing were used to detect AR mutations. RESULTS: Our study revealed the average AR expression in the prostate adenocarcinoma was 52.2 +/- 27.1%, which was significantly lower than that in the adjacent non-tumorous prostate tissue (68.3 +/- 18.3% in average) (P < 0.001). A significant correlation was obtained between progression-free survival and AR expression (P < 0.01). By SSCP analysis, three silent mutations (T649T, E709E and E711E) were detected in three separate prostate carcinomas. CONCLUSION: : We conclude that AR expression is a useful prognostic indicator for tumor progression. Androgen receptor mutation may be an uncommon molecular event in untreated prostate cancer in Japanese men.     

晚期前列腺癌联合雄激素阻断治疗的长期随访

目的:了解晚期前列腺癌联合雄激素阻断治疗的长期生存率。方法:选取1993年1月~2000年1月初采用联合雄激素阻断治疗的59例前列腺腺癌患者,其中28.81%和45.76%为临床局部晚期(T3-4 N0M0期)和转移(TxNxM+期)病例,全部随访5年以上。结果:全组病例3、5、7年的总体生存率分别是79.36%、61.46%、49.15%,其中,临床局部晚期和转移者的5年生存率分别为80.77%和32.65%,而高分化腺癌和低分化腺癌的5年生存率分别为86.21%和30%(P<0.01)。另外,PSA>30μg/L时其长期生存率有明显下降趋势。结论:采用内分泌治疗的晚期前列腺癌,病理低分化、临床分期达T3 c-4NxMx或TxNxM+期及PSA>30μg/L均提示预后较差,晚期前列腺癌病例的治疗应综合多因素,选择个体化方案。     

Molecular biology of progression of prostate cancer.

Despite the clinical importance of prostate cancer, the molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. The lack of knowledge on the mechanisms has probably been one of the most important reasons why no new treatment modalities have been developed to cure the disease. Recent studies, especially those performed by comparative genomic hybridization, have revealed the frequent chromosomal alterations that most likely harbor the genes critical for the progression of prostate cancer. Such genetic aberrations include losses of 8p, 10q, 16q, and 13q as well as gains of 7p, 7q, 8q, and Xq. Unfortunately, the target genes for these alterations are, in most of the cases, not known. We have recently identified the androgen receptor (AR) gene as a target gene for the Xq12 amplification found in one-third of the hormone-refractory prostate cancer. The findings suggest that the AR gene amplification and overexpression is involved in the emergence of hormone-refractory prostate cancer.