Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A relationship between the two tumours has been suggested in the literature. This study investigated the clonality of both the stroma and the epithelium of these fibroepithelial tumours and attempted to construct a model in which fibroadenoma can progress in both an epithelial and a stromal direction. Fibroadenomas (n=25) and phyllodes tumours (n=12) were selected for analysis. Tissue was microdissected and analysed for clonality using a polymerase chain reaction (PCR)-based assay targeted at an X-linked polymorphic marker, the human androgen receptor gene (HUMARA). Nineteen fibroadenomas and nine phyllodes tumours could be analysed. Normal-appearing epithelium, hyperplastic epithelium, and stroma removed from fibroadenomas were polyclonal. As expected, carcinoma in situ (CIS) removed from four fibroadenomas was monoclonal. Three areas of apparent stromal expansion within fibroadenoma were monoclonal, suggesting stromal progression. Mostly, the stroma of phyllodes tumours was monoclonal and the epithelium polyclonal. In two cases, however, the epithelium seemed to be monoclonal, whereas in three other cases the stromal component was polyclonal. These findings indicate that fibroadenoma can progress in an epithelial direction to CIS and in a stromal direction to phyllodes tumour.
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PMID:Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay. 1221 75

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.
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PMID:Androgen receptors in prostate cancer. 1223 44

The aim of this study was to examine the prevalence of androgen receptor (AR) amplification in metastases to bone and other sites in patients with hormone-refractory prostate cancer (HRPC) and to compare these findings with those in pretreatment primary tumour samples from the same patients. Tissue from 24 patients with HRPC was available for study, together with 13 primary tumour specimens. AR gene amplification and copy number for X-chromosome were assessed by fluorescence in situ hybridization (FISH) using a SpectrumOrange-labelled probe at locus Xq11-13 for the AR gene and a SpectrumGreen-labelled alpha-satellite probe for the X-chromosome (Vysis, UK, Ltd.). A minimum of 20 nuclei were scored in each of three tumour areas by two independent observers. Samples from 18/24 patients with HRPC (12 bone marrow biopsies, three local tumour recurrences, and three lymph nodes) and nine primary tumour specimens were adequate for FISH analysis. Results were expressed as a mean ratio of AR gene copy number : mean X-chromosome number, with a ratio of greater than 1.5 defined as amplification. AR gene amplification was seen in 9/18 (50%) cases of HRPC and in none of the primary (untreated) tumour specimens (p = 0.0048, Fisher's exact test). For the 12 bone marrow samples, AR gene amplification occurred in 5/12 (38%) cases. Elevated copy number for chromosome X occurred in 3/18 (17%) HRPC and 4/9 (44%) matched primary tumours. This study shows for the first time that AR gene amplification can be demonstrated by FISH in bone metastases from HRPC patients. Because bone marrow biopsies can be obtained from most patients with HRPC, the findings provide a rational basis for the routine selection of patients who may respond more favourably to second-line anti-androgen therapy.
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PMID:Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. 1223 84

Recent technological advances now allowing both large scale data generation and its in-depth analysis have opened new avenues to identify and target genes involved in neoplastic transformation and tumor progression. This accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer agents. It is anticipated, that these agents will show enhanced specificity for malignant cells and a more favorable side-effect profile due to well-defined and tailored modes of action. Antisense oligonucleotides (ASOs) are short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene are close, after decades of challenges, close to fulfilling their promise in the clinical setting. Emerging clinical evidence supports the notion that ASOs stand a realistic chance of developing into one of the main players of rationally designed anti-cancer agents, although certainly not all of the challenges have been met to date. The status of antisense targeting of genes relevant to prostate cancer, including bcl-2, bcl-xL, clusterin, androgen receptor (AR) and IGFBPs, are reviewed.
Cancer Metastasis Rev 2002
PMID:Antisense therapy: current status in prostate cancer and other malignancies. 1240 Sep 97

The ability to manipulate gene expression in specific cell types at specific times utilizing transgenic technology has allowed the development of novel mouse model systems that can mimic human disease. We have previously established the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model for prostate cancer using the rat probasin promoter to direct expression of the SV40 early genes to prostate epithelium. Male TRAMP mice exhibit consistent prostate-specific patterns of expression and develop prostatic intraepithelial neoplasia that will become invasive and metastasize primarily to the lymph nodes and lungs. In this paper we report our continued experience with this model and present a standardized histologic grading system to designate low and high grade prostatic intraepithelial neoplasia and well, moderate, and poorly differentiated prostate adenocarcinoma. In addition, we demonstrate the persistence of androgen receptor expression during pathologic progression and characterize heterogeneous cytokeratin expression in localized and metastatic prostate cancer. Finally, we report on our observations that phenotypic variability in tumor and pathologic progression in TRAMP occurs as a function of genetic background.
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PMID:Pathologic progression of autochthonous prostate cancer in the TRAMP model. 1249 41

Steroid hormones and their receptors are involved as initiators or promoters in prostate carcinogenesis. The intrauterine-perinatal period and maternal estrogen and testosterone levels have been proposed to be of etiologic importance in prostate tumorigenesis and cancer progression. The objective of this study was to analyze genetic polymorphisms in the androgen receptor ARStuI by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and in the estrogen receptor ER325 by PCR-single-strand conformational polymorphism (PCR-SSCP). In our study of 170 prostate cancer patients, ARStuI and ER325 genotypes and their association with disease progression and metastasis were analyzed. Age-adjusted logistic regression analysis indicates the association of ARStuI S1 allele with high-grade tumor (P = 0.033; OR = 3.0, 95% CI = 1.1-8.3) and the association of ER325 with high-grade tumor (P = 0.003; OR = 3.0, 95% CI = 1.4-6.4), advanced disease (P = 0.020; OR = 2.4, 95% CI = 1.1-5.1), risk of progression (P = 0.027; OR = 2.5, 95% CI = 1.1-5.7) and the presence of metastatic disease (P = 0.006; OR = 3.1, 95% CI = 1.4-6.8). In summary, this study has demonstrated androgen receptor (ARStuI) and estrogen receptor (ER325) genetic polymorphisms in prostate cancer patients and its association with disease progression and metastasis. Our results support the hypothesis that genetic factors related to steroid hormone receptors may influence the behavior of human prostate cancer.
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PMID:Steroid hormone genotypes ARStuI and ER325 are linked to the progression of human prostate cancer. 1260 25

Prostate cancer is the most common cancer diagnosed in American males, and is the second leading cause of cancer-related deaths. Most patients who develop metastatic disease will initially respond to androgen deprivation, but response is invariably temporary. Most patients will develop androgen-independent ("hormone-refractory") disease that results in progressive clinical deterioration and ultimately death. This progression to androgen independence is accompanied by increasingly evident DNA instability and alterations in genes and gene expression, including mutations in p53, over-expression of Bcl2, and mutations in the androgen receptor gene, among others. Treatment options for hormone refractory disease include intensive supportive care, radiotherapy, bisphosphonates, second-line hormonal manipulations, cytotoxic chemotherapy and investigational agents. A post-treatment reduction in the level of prostate specific antigen (PSA) by 50% has been shown to correlate with survival and has been accepted by consensus as a valid endpoint in clinical trials. Chemotherapeutic agents such as mitoxantrone, estramustine, and the taxanes have yielded improved response rates and palliative benefit, but not improved survival. Therefore, current efforts must be focused on enrolling patients onto clinical trials of investigational agents with novel mechanisms of action, and on using survival, time to progression, and quality of life as end points in routine clinical practice.
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PMID:Current strategies in the management of hormone refractory prostate cancer. 1278 12

Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer. Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.
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PMID:Androgen receptor involvement in the progression of prostate cancer. 1279 Jul 84

The most significant discovery of the second half of the XXth century in the field of prostate cancer therapy is probably the observation that the human prostate, as well as many other peripheral human tissues, synthesize locally an important amount of androgens from the inactive steroid precursors dehydroepiandrosterone (DHEA) and its sulfate DHEA-S. In parallel with these observations, two important discoveries also made by our group are applied in the clinic worldwide, namely the use of LHRH (luteininizing hormone-releasing hormone) agonists to completely block testicular androgens, while, simultaneously, the androgens made locally in the prostate from DHEA are blocked in their access to the androgen receptor by a pure antiandrogen of the class of flutamide. This treatment, called combined androgen blockade, has been the first treatment demonstrated to prolong life in prostate cancer. While the first studies were performed in patients with advanced and metastatic disease, our recent data indicate a remarkable level of efficacy of the same treatment applied to localized prostate cancer, namely a 90% possibility of cure. However, in order to be able to treat localized prostate cancer, early diagnosis must be achieved. In the first large-scale randomized study of prostate cancer screening, we have demonstrated that 99% of prostate cancers can be diagnosed at the localized or potentially curable stage, using simple annual measurement of PSA (prostatic specific antigen). Today's data show that with the simple application of the available diagnostic and therapeutic tools, death from prostate cancer should be an exception.
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PMID:[From the gene to the clinic: prostate cancer death can now be an exception?]. 1461 99

Androgen action is mediated through androgen receptor (AR), which appears to undergo structural and functional alterations during prostate cancer (CaP) progression. AR mutations have been infrequently reported in CaP before hormonal therapy, but in untreated, advanced tumors AR mutations are suggested to be more common. To investigate the frequency of AR mutations in aggressive CaP before hormonal therapy, we have analyzed AR coding region for aberrations in 21 paraffin-embedded prostate carcinoma samples (14 primary tumors, 7 metastases) of poor histologic differentiation. Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis. Mutations resided in the transactivation domain and in the hinge region. One of the hinge region mutants, Ser646Phe, that was identified in a patient with short endocrine therapy response, exhibited a markedly increased transcriptional activity on single androgen response element-containing promoters. In conclusion, AR mutations are frequent in high-grade CaP before initiation of hormonal therapy, and these mutations may play a role in poor therapy response and emergence of hormone-refractory CaP in some cases.
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PMID:Androgen receptor mutations in high-grade prostate cancer before hormonal therapy. 1469 Dec 88


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