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PubMed2001

Identification of a novel gene with increasing rate of suppression in high grade prostate cancers.

Prostate cancer is the second leading cause of cancer-related deaths in the United States. However, the underlying molecular events for prostate cancer development are not clear. In this study, we applied the recently developed technology known as differential subtraction chain (DSC) to identify a novel gene whose expression is inactivated in high grade prostate cancer. This gene, designated as SAPC, is expressed in normal prostate acinar cells. Its expression is dramatically down-regulated in high grade prostate cancers (4/4) but is unaltered in low grade prostate cancers. It encodes a 7.7-kd protein. Its sequence shares some homology with the cysteine-rich domain of 2-5A-dependent RNase L, which is a critical component of the interferon-induced apoptosis cascade. The selective inactivation in the more aggressive prostate cancers holds promise for SAPC as a potential prognostic marker for high grade prostate cancer.

Amino Acid Sequence↗

PubMed2004

New features in the treatment of androgen-independent prostate cancer.

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the cancer is diagnosed at a more advanced age. Prostate cancer evolves from an androgen dependant stage to stage where it escapes from all anti-androgenic treatments. The patient usually dies within two years following the diagnosis of advanced cancer. Therefore, it is of great interest to develop new therapies for androgen independent prostate cancer. The androgen independent evolution of prostate cancer is a complex phenomenon at the cellular and molecular levels. It includes an increased sensitivity to growth factors, the control of proliferation pathways, apoptotic and survival pathways as well as the control of angiogenesis. Epidemiological studies have also suggested that certain vitamins or phyto-oestrogens could protect against prostate cancer development. The present review attempts to present an overview of the fundamental research in cellular signalling which could be interesting as target for the treatment of androgen independent prostate cancer. Also the potential interest of non-androgenic steroids was reviewed for the same goal.

Androgens↗

PubMed1991

Searching for suppressor genes in prostate cancer.

Prostate cancer poses many challenges for clinicians. Methods for early detection are not satisfactory, and in fact more efficient detection will lead to even further dilemmas. We know from necropsy studies that the occurrence of prostate cancer is much higher than the clinical incidence (Yatani et al, 1982). Obviously, only some of the prostate cancers detected early would progress to a health threatening state if left untreated--the question is, which ones? This is a question that must be addressed, because prostate cancer has the highest occurrence rate of any cancer among males in the US, and current approaches to eradicating early stage prostate cancers involve expensive surgical or irradiation techniques. Even for primary prostatic tumours of more advanced stages, current prognostic indicators are not ideal. What is the potential of specific suppressor genes lost in prostate cancer for identifying useful prognostic indicators? Even though numerous molecular events, including loss as well as gain of gene activity, have been delineated for colon cancer, no single genetic change has proven prognostic. Rather, increasing malignant potential of colon cancer seems to be correlated with an accumulation of several genetic events. On the other hand, a specific chromosomal abnormality, a deletion of chromosome 17p, does appear to be a prognostic indicator for distinguishing high grade from low grade transitional cell carcinoma (Olumi et al, 1990). Whether loss of chromosome 17p will prove to be a better prognostic marker than other parameters, however, is still unknown. At present, no consistent genetic changes have been associated with any stage of prostate cancer, so we are a long way from determining whether such changes will prove their hypothetical usefulness as new and improved prognostic indicators. The other clinical realm in which the identification of loss of suppressor genes in prostate cancer might prove a resource is therapy. Suppressor gene products obviously provide key regulatory functions, perhaps linked to differentiation, in normal cells. Restoration of these regulatory functions in cancer cells, either by directly supplying the lost regulatory element or by circumventing the missing element by other means, is a novel therapeutic approach that might offer hope even in metastatic disease. Realization of this dream will require much more knowledge of the precise nature of the suppressor gene products lost in cancer, and a detailed understanding of the hierarchy of regulation of growth and differentiation in normal cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Transformation, Neoplastic↗

PubMedDate not supplied

Male patients with diagnoses of both breast cancer and prostate cancer.

Recently cancer susceptibility syndromes have been characterized that suggest possible genetic linkages between breast cancer and prostate cancer within families. Despite these connections, male breast cancer and prostate cancer in an individual man has rarely been reported. The clinical features of 10 patients with both of these cancers are described here. One hundred sixty-one patients with male breast cancer were seen at the Dana-Farber Cancer Institute and Massachusetts General Hospital between 1977 and 2000. Of these, 10 were identified who also had prostate cancer. A retrospective review of records from these 10 patients was performed. Breast cancer preceded prostate cancer in eight of these men. The mean age of diagnosis of breast cancer was 65.7 years (range 47-72 years). Twenty percent had nodal involvement at diagnosis and two patients ultimately developed evidence of metastatic disease. The mean age of diagnosis of prostate cancer was 68.0 years (range 51-76 years) with a median prostate-specific antigen (PSA) level at diagnosis of 6 ng/ml (range 1.8-47.5 ng/ml). Seven patients had a family history of female breast cancer in a first-degree relative, while one had a family history of prostate cancer. At a median follow-up of 6.5 years from initial cancer diagnosis, one patient had died of metastatic breast cancer and another had died of metastatic prostate cancer. The clinical features and course of the breast cancers diagnosed in this series do not appear significantly different from those described for the general population of male breast cancer patients. In addition, these men do not appear to develop prostate cancer at an earlier age or more aggressive stage than the general population.

Adenocarcinoma↗

PubMed2004

No major association between TGFBR1*6A and prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer.

Activin Receptors, Type I↗

PubMed2001

Expression and regulation of prostate androgen regulated transcript-1 (PART-1) and identification of differential expression in prostatic cancer.

Prostate androgen regulated transcript 1 (PART-1), is a gene predominantly expressed in the prostate gland and is regulated by androgens in human prostate cancer cell lines. Here, we report additional characteristics of PART-1 tissue expression and hormonal regulation and study its expression profile in human normal and matched prostate cancer tissues. Since PART-1 shows similarity to prostate-specific antigen (PSA) in prostate specificity and regulation, we hypothesized that it may be implicated in prostate carcinogenesis or may be a potential new biomarker. We used reverse transcriptase polymerase chain reaction (RT-PCR) to further characterize PART-1 tissue expression and hormonal regulation in the LNCaP prostate cancer cell line. RT-PCR analysis revealed that PART-1 is expressed not only in the prostate and salivary gland, but also in other tissues, including the thymus and placenta. In addition to androgen stimulation, PART-1 is also up-regulated by progestins, oestrogens and glucocorticoids. We further studied the expression of PART-1 in 27 paired (from the same patient) cancerous and non-cancerous prostatic tissues, with qualitative and quantitative RT-PCR (LightCycler technology), in order to examine whether PART-1 is overexpressed or underexpressed in cancer. Our results indicated that PART-1 is more frequently overexpressed in the cancerous prostatic tissue. We conclude that this gene is overexpressed in prostate cancer and may represent a novel prostate cancer tumour marker.

Aged↗

PubMed2006

Prevention, complementary therapies, and new scientific developments in the field of prostate cancer.

Prostate cancer prevention and therapies were reviewed in a recent update. Finasteride, a 5alpha reductase inhibitor, shows promise as a preventative; however, it may increase the incidence of high-grade cancer. There are ongoing studies regarding the positive effects of antioxidant therapy (vitamin E, selenium, and lycopene) on the prevention of prostate cancer; initial results are promising. Lipid-lowering drugs are associated with a statistically significant reduction in prostate cancer incidence, a 46% reduction in risk of high-grade or high-stage prostate cancer, and a 66% reduction in mortality from prostate cancer. Overexpression of transcription factors is caused by translocation of the promoter of the TMPRSS2 gene, which may be a primary event in prostate cancer. Immunomic profiling with use of autoantibodies directed against prostate-specific antigens may be used to identify cases of prostate cancer.

Journal Article↗

PubMed2004

The complex genetic epidemiology of prostate cancer.

Prostate cancer is the most frequent cancer among men in most developed countries, yet little is known about its causes. Older age, African ancestry and a positive family history of prostate cancer have long been recognized as important risk factors. The evidence that genetics probably plays a critical role is based on a variety of study designs, including case-control, cohort, twin and family-based, all of which are reviewed in detail. The search for prostate cancer susceptibility genes by linkage studies offered early hope that finding genes would be as 'easy' as finding genes for breast cancer and colon cancer susceptibilities. However, this hope has been dampened by the difficulty of replicating promising regions of linkage. This review provides updates on recent developments, and a broad view of the disparate findings from different linkage studies. Early linkage results have provided targeted candidate regions for prostate cancer susceptibility loci, including HPC1 on chromosome 1q23-25, PCAP on chromosome 1q42-43, CAPB on chromosome 1p36, linkage to chromosome 8p22-23, HPC2 on chromosome 17p, HPC20 on chromosome 20q13, and HPCX on chromosome Xq27-28. These linkage findings lead to refined mapping and mutation screening of several strong candidate genes, including ELAC2, RNASEL and MSR1. Up to now, a total of 10 genome-wide linkage scans for prostate cancer susceptibility have been completed, and are reviewed. Furthermore, recent findings that Gleason's grade, a measure of aggressiveness of prostate cancer, is linked to several genomic regions are reviewed. Finally, the roles of environmental and dietary risk factors, and common genetic polymorphisms of genes likely to play a role in common forms of prostate cancer, are briefly discussed within in the context of searching for genes that influence prostate cancer risk.

Epidemiologic Studies↗

PubMedDate not supplied

CYP17 gene promoter allelic variant is not associated with prostate cancer.

Prostate cancer is the most common urological malignancy in Taiwan. The formation of prostate cancer has been reported to be associated with androgen. Two key steps in the sex steroid synthesis are mediated by the enzyme cytochrome p450c17alpha which is encoded in the CYP17 gene. Our aim was to investigate whether a polymorphism of CYP17 gene could be used as a genetic marker for associating prostate cancer. In this study, we compared the frequency of the C/T polymorphism of CYP17 gene 5'-UTR promoter region between 93 patients with prostate cancer and 121 healthy male volunteers (age, >60 years). The result revealed no significant association between the CYP17 genotype and prostate cancer (P =.781). Therefore, CYP17 C/T polymorphism is not a valid genetic marker for prostate cancer. Although a possible interaction between CYP17 gene C/T polymorphism and SP-1 transcription factor has been reported in the literature, we did not find any evidence for this the difference among clinical staging, pathological grading, or responsiveness to hormonal therapy in prostate cancer.

3' Untranslated Regions↗

PubMed1991

Endocrine therapy for prostate cancer.

Prostate cancer is the most frequent cancer in men. A discovery of major importance in the endocrinology of prostate cancer is that the testes contribute only 60% of total androgens in adult men; the remaining 40% are synthesized in peripheral tissues, including the normal and cancerous prostate, from inactive androgen precursors of adrenal origin. Using a combination therapy that includes a pure blocker of the androgen receptor or antiandrogen and castration (medical with luteinizing hormone-releasing hormone agonist or surgical by orchiectomy), the duration of response and survival have been demonstrated to be prolonged for the first time in advanced prostate cancer.

Androgen Antagonists↗

PubMed2005

Who is the average patient presenting with prostate cancer?

Prostate cancer screening, diagnosis, and treatment have changed dramatically in the last 20 years. Patients with newly diagnosed prostate cancer have many treatment options available. We attempted to determine how patient demographics and quality of life (QOL) have changed, and we describe the average patient with newly diagnosed prostate cancer in the early 21st century. From the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) we identified 3003 men with prostate cancer diagnosed between 1997 and 2003 for whom pretreatment demographic and QOL data were available. All patients completed both the University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) and the Rand Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) as self-administered questionnaires at the time of diagnosis. We compared demographic variables (age at diagnosis, race/ethnicity, education, number of comorbidities, body mass index [BMI], and insurance type), treatment choice, and pretreatment QOL scores on the SF-36 and UCLA-PCI scales for the periods 1997 to 1999 or 2000 to 2003. Stratified analysis by risk category was performed for demographic and QOL data for the 2 periods. Race/ethnicity and insurance demographics were statistically different for the 2 periods. Low-risk patients also showed a statistically increased BMI in the 2000 to 2003 period. Risk category predicted performance on both inventories, with low-risk patients having better function than intermediate-risk patients and high-risk patients in the areas of urinary bother, bowel function and bother, and sexual function and bother, as well as in many general well-being and emotional health scales on the SF-36. We conclude that the "average" prostate cancer patient is white, 65 years of age, overweight, educated at a college level, and has 1 to 2 comorbidities. Patients report average or above-average pretreatment health-related QOL for all scales based on 2 validated instruments. In this cohort, more patients chose radical prostatectomy than any other form of treatment.

Aged↗

PubMed2002

Chemoprevention strategies for prostate cancer.

Prostate cancer is the most common male malignancy in western countries. Although primary prevention of prostate cancer is not possible, screening using prostate-specific antigen (PSA) may eliminate prostate cancers by definitive treatments. Prevention of clinically detectable prostate cancer requires earlier chemoprevention interventions. Because prostate cancer is histologically present in 30-50% of 30- to 50-year-old men, effective chemoprevention needs to inhibit not only prostate carcinogenesis but also growth and progression of these cancers. A prostate carcinogenesis animal model has been used to screen chemopreventive agents; inhibitory effects were found with 9-cis-retinoic acid, dehydroepiandrosterone, fluasterone, and the Bowman-Birk inhibitor and an isoflavone mixture which both occur in soy. Such results can be used to select agents for clinical trials. Besides large-scale long-duration prevention trials, trials of short/intermediate duration using smaller cohorts prior to or following radical prostatectomy may provide excellent and cost-effective approaches for chemopreventive agent efficacy testing. Intervention prior to surgery allows measurements of intervention agents and intermediate end-points in the prostate. These peri-surgical trials only assess inhibition of growth and progression of preexisting cancer, not real preventive effects, but they focus on clinically significant cancers. Such trials are an essential step in the development of antiprostate cancer chemoprevention agents.

Adenocarcinoma↗

PubMed1997

Is exercise beneficial in the prevention of prostate cancer?

Prostate cancer is the most frequently diagnosed cancer in men. Exercise has been studied as an alterable risk factor that may reduce the incidence, morbidity and mortality due to this cancer. Epidemiological studies play an important role in assessing the relationship between physical activity and prostate cancer. Studies have attempted to estimate physical activity level by measuring time spent in sports, leisure or occupational activity. We identified 17 studies that assessed the effect of exercise on the development of prostate cancer. Although methodological limitations could be identified in most of the studies, 9 suggested that exercise may be beneficial in decreasing prostate cancer risk, while 5 were null providing no conclusive evidence and 3 actually showed an increased risk of prostate cancer with increased physical activity. The bulk of the evidence at this time does not seem to support an overwhelmingly beneficial effect of exercise on prostate cancer risk. Future studies need to investigate the frequency, intensity and duration of physical activity as well as the type of activity and period during a man's lifetime when exercise might be beneficial. It is reasonable to conclude that exercise may be a potential factor that can be modified to prevent prostate cancer and it seems prudent to recommend that all men become physically active.

Exercise↗

PubMed2006

Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer.

Prostate cancer is an androgen-dependent disease; metastatic prostate cancer is typically treated by androgen receptor (AR) blockade. Recurrence after androgen ablation and evidence that AR continues to play a role in many prostate cancers has led to an examination of other factors that potentiate AR activity. AR is a ligand-activated transcription factor whose activity is regulated not only by hormone but also by the levels of coactivators recruited by AR to facilitate transcription. We sought to assess the consequences of reducing expression of the transcription intermediary factor 2 (TIF2) coactivator on prostate cancer cell growth and AR action in cell lines to examine TIF2 expression in prostate cancer and to correlate expression with clinical outcome. Depletion of TIF2 reduced expression of AR-induced target genes and slowed proliferation of AR-dependent and AR-independent prostate cancer cells. Remarkably, we found that TIF2 expression is directly repressed by high levels of androgens in multiple AR-expressing cell lines. Expression of a reporter containing 5'-flanking region of the TIF2 was repressed both by androgens and by the antagonist, Casodex. Expression of TIF2 correlates with biochemical (prostate-specific antigen) recurrence (P = 0.0136). In agreement with our in vitro findings, the highest expression of TIF2 was found in patients whose cancer relapsed after androgen ablation therapy, supporting the idea that AR blockade might activate pathways that lead to stimulation of AR-dependent and AR-independent proliferation of prostate epithelium. The elevated expression of TIF2 at low hormone levels likely aids in inducing AR activity under these conditions; treatment with Casodex has the potential to counteract this induction.

Androgens↗

PubMedDate not supplied

The role of vitamin D in prostate cancer.

Prostate cancer is the second leading cause of cancer deaths in men in the United States. Developing new treatment strategies is critical to improving the health of men. This article will be a general review of the field with a focus on research from our laboratory. Our research has focused on four areas in which we have pursued the possible use of 1alpha,25(OH)(2)D(3) and its analogs to treat prostate cancer: 1) The ability of 1alpha,25(OH)(2)D(3) to up-regulate androgen receptors in LNCaP human prostate cancer cells. The implications of this finding on 1alpha,25(OH)(2)D(3)'s ability to inhibit cell growth in vivo are unclear at present.2) The reasons for an inability of 1alpha,25(OH)(2)D(3) to inhibit DU 145 prostate cancer cell growth were explored. We found that combination of an imidazole drug, Liarozole, with 1alpha,25(OH)(2)D(3) was capable of inhibiting DU 145 cell growth.3) A number of low-calcemic vitamin D analogs exhibit potent anti-proliferative activity on prostate cancer cells. We have developed a novel approach using the yeast two-hybrid system to screen for potent analogs.4) The results of a clinical trial of 1alpha,25(OH)(2)D(3) treatment of patients with early recurrent prostate cancer. We provide preliminary evidence that 1alpha,25(OH)(2)D(3) may be effective in slowing the rate of PSA rise in selected cases of prostate cancer. In conclusion, we believe that 1alpha,25(OH)(2)D(3) has a role in the treatment and/or prevention strategies being developed for prostate cancer. However, to increase antiproliferative potency without increasing side-effects, the use of less calcemic analogs appears to be the most reasonable approach.

Antineoplastic Agents↗

PubMed2001

Interleukin-6 is an autocrine growth factor in human prostate cancer.

Prostate cancer is the most common cancer in American men and the second leading cause of cancer deaths in this group. We have found that interleukin (IL)-6 protein concentrations are increased approximately 18-fold in clinically localized prostate cancers when compared to normal prostate tissue. Normal and neoplastic prostatic epithelial cells in culture, with the exception of LNCaP cells, secrete IL-6. Addition of exogenous IL-6 to primary epithelial cells in culture or the LNCaP prostate cancer cell line leads to phosphorylation of Stat-3 and increases in net cell proliferation. The concentration of IL-6 receptor is increased eightfold in the prostate cancer tissues and is increased in the cancer cells by immunohistochemistry. The increased expression of IL-6 receptor is correlated with increased proliferation of prostate cancer cells in vivo as assessed by Ki67 immunohistochemistry. These findings strongly support the hypothesis that IL-6 acts as a significant autocrine growth factor in vivo for primary, androgen-dependent prostate cancers.

Cell Division↗

PubMedDate not supplied

Androgen receptor as a therapeutic target for androgen independent prostate cancer.

Prostate cancer is the leading cause of nonskin malignancy and the second leading cause of cancer death in men. Androgen deprivation therapy is the first-line of systemic therapy against advanced prostate cancer. All advanced prostate cancers eventually grow despite castrate levels of testosterone. We review the evidence that androgen independent prostate cancer continues to require androgen receptor activity for growth, the mechanisms of androgen receptor activation in the castrate setting, and possible points of intervention for novel therapies targeting the androgen receptor and prostate cancer.

Aged↗

PubMed1992

Prostate specific antigen: clinical use in the diagnosis and management of prostate cancer.

Prostate specific antigen (PSA) has replaced prostatic acid phosphatase as the preeminent clinical tumor marker in the management of patients with prostate cancer. Serum PSA levels have been shown to be proportional to clinical and pathologic stage of prostate cancer and in particular to correlate closely with prostate cancer volume. Serum levels of PSA thus serve as a useful adjunct in the initial clinical staging of men with prostate cancer. Serum PSA values provide a unique and valuable tool in monitoring prostate cancer progression over time and its response to surgical, radiation, and/or hormonal therapies. Unfortunately, its lack of specificity for prostate cancer leaves many questions unanswered as to the efficacy and advisability of using PSA as a screening test for this cancer.

Aged↗