Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division, but the specific genes involved in progression of hormone-related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and prevention of hormonal carcinogenesis are discussed. This includes developing polygenic models of cancer predisposition and the further development of safe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizing that functionally relevant sequence variants in genes involved in steroid hormone metabolism and transport would act together, and also interact with well-known hormonally related risk factors, to define a high-risk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinically useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17alpha (CYP17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5alpha-reductase type II (SRD5A2), CYP17 and the 3beta hydroxysteroid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic cohort to support these models.
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PMID:Hormonal carcinogenesis. 1123 97

The androgen-signaling pathway is important for the growth and progression of prostate cancer cells. The growth-promoting effects of androgen on prostate cells are mediated mostly through the androgen receptor (AR). There is increasing evidence that transcription activation by AR is mediated through interaction with other cofactors. beta-Catenin plays a critical role in embryonic development and tumorigenesis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Here, we demonstrate that a specific protein-protein interaction occurs between beta-catenin and AR. Unlike the steroid hormone receptor coactivator 1 (SRC1), beta-catenin showed a strong interaction with AR but not with other steroid hormone receptors such as estrogen receptor alpha, progesterone receptor beta, and glucocorticoid receptor. The ligand binding domain of AR and the NH(2) terminus combined with the first six armadillo repeats of beta-catenin were shown to be necessary for the interaction. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. Moreover, expression of E-cadherin in E-cadherin-negative prostate cancer cells results in redistribution of the cytoplasmic beta-catenin to the cell membrane and reduction of AR-mediated transcription. These data suggest that loss of E-cadherin can elevate the cellular levels of beta-catenin in prostate cancer cells, which may directly contribute to invasiveness and a more malignant tumor phenotype by augmenting AR activity during prostate cancer progression.
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PMID:Linking beta-catenin to androgen-signaling pathway. 1179 9

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.
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PMID:2-Methoxyestradiol, a promising anticancer agent. 1258 5

The development of chemoprevention strategies against prostate cancer would have the greatest overall impact both medically and economically against prostate cancer. Estrogens are required for prostate carcinogenesis. Estrogenic stimulation through estrogen receptor alpha in a milieu of decreasing androgens contributes significantly to the genesis of benign prostatic hyperplasia, prostate dysplasia, and prostate cancer. The ability of antiestrogens and selective estrogen receptor modulators (SERMs) to delay and to suppress prostate carcinogenesis is supported by preclinical, clinical, and epidemiological studies. SERMs have many features that make them attractive candidates for prostate cancer chemoprevention including their favorable safety profile and efficacy in preclinical prostate cancer models. The true clinical benefits of SERMs for chemoprevention to prevent prostate cancer, however, should continue to be investigated through human clinical trials. A phase IIb/III human clinical trial is currently evaluating safety and efficacy of toremifene, a SERM, in men who have high-grade prostatic intraepithelial neoplasia.
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PMID:Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk. 1275 92

Multiple promoters and differential splicing of 5' upstream exons are often found in various nuclear receptor genes including steroid receptors. Three promoters control the expression of human estrogen receptor alpha (ERalpha) isoforms: ERalpha-A, ERalpha-B, and ERalpha-C, and two promoters control the expression of human progesterone receptor (PR) isoforms: PR-A and PR-B. The expression levels of these isoforms differ with respect to each other in certain target tissues. The role of these isoforms may differ in various types of cells and tissues. The ER and PR contain CpG islands in the 5' upstream regions. One possible mechanism for changing the transcriptional status is methylation of CpG-enriched regions in these isoforms. We have investigated the expression and methylation status of the three different ERalpha promoters and the two different PR gene promoters by using methylation specific PCR (MSP) and direct DNA sequencing in several endometrial and prostate cancer cell lines and tissues. The results of these experiments suggest that ERalpha-A, ERalpha-B, and PR-A were expressed and ERalpha-C and PR-B were inactivated in endometrial cancers. To the contrary, ERalpha-A and ERalpha-B were inactivated and ERalpha-C, PR-A and PR-B were expressed in all prostate cancer. Treatment with demethylating agent (5-aza-2'-deoxycytidine) restored these gene expressions, suggesting that inactivation of this gene is through methylation. Our MSP and direct DNA sequencing showed that ERalpha-A, ERalpha-B, and PR-A genes were unmethylated and ERalpha-C and PR-B were methylated in endometrial cancers although ERalpha-A and ERalpha-B were methylated and ERalpha-C, PRA and PRB were unmethylated in prostate cancers. These reports clearly demonstrate that selective hypermethylation can selectively silence multiple promoters of steroid receptors in carcinogenesis.
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PMID:Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. 1277 Jul 52

Paxillin, a member of the group 3 subfamily of LIM domain proteins, is localized within focal adhesions and participates in a number of signal transduction pathways mobilized upon activation of cell surface receptors. In recent years, a number of group 3 LIM domain proteins have been found to also localize within the nucleus and exert direct effects on transcription. We show here that paxillin is present within nuclei and can target the nuclear matrix of CV-1 cells, cultured prostate cancer cell lines, and human prostate tissue. The increased targeting of androgen receptor to the nuclear matrix upon overexpression of paxillin may be brought about by direct interactions between paxillin and the receptor, which were detected in vitro. Paxillin functions as a coactivator for androgen receptor and glucocorticoid receptor, but not estrogen receptor alpha, similar to its close relative Hic-5/ARA55. Both paxillin and Hic-5/ARA55 use their COOH-terminal LIM domain to interact with steroid receptors. However, paxillin is distinguished from Hic-5/ARA55 by both the location of its receptor coactivation domain (i.e., COOH-terminal LIM domain) and by the dominant-negative activity of its NH(2)-terminal domain. Thus, highly related group 3 LIM domain proteins may use distinct mechanisms to modulate steroid hormone receptor transactivation.
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PMID:The Group 3 LIM domain protein paxillin potentiates androgen receptor transactivation in prostate cancer cell lines. 1294 17

Post-translational modification of chromatin histones governs a key mechanism of transcriptional regulation. Histone acetylation, together with methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, and ADP ribosylation, modulate the activity of many genes by modifying both core histones and non-histone transcription factors. Epigenetic protein modification plays an important role in multiple cellular processes including DNA repair, protein stability, nuclear translocation, protein-protein interactions, and in regulation of cellular proliferation, differentiation and apoptosis. Histone acetyltransferases modify histones, coactivators, nuclear transport proteins, structural proteins, cell cycle components and transcription factors including p53 and nuclear receptors. The estrogen, PPARgamma and androgen receptor are members of the nuclear receptor (NR) superfamily. The androgen receptor (AR) and estrogen receptor alpha (ERalpha) are directly acetylated by histone acetyltransferases at a motif that is conserved between species and other NR. Point mutations at the lysine residue within the acetylation motif of the AR and ERalpha have been identified in prostate cancer as well as in breast cancer tissue. Acetylation of the NR governs ligand sensitivity and hormone antagonist responses. The AR is acetylated by p300, P/CAF and TIP60 and acetylation of the AR regulates co-regulator recruitment and growth properties of the receptors in cultured cells and in vivo. AR acetylation mimic mutants convey reduced apoptosis and enhanced growth properties correlating with altered promoter specificity for cell-cycle target genes. Cell-cycle control proteins, including cyclins, in turn alter the access of transcription factors and nuclear receptors to the promoters of target genes.
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PMID:Acetylation of nuclear receptors in cellular growth and apoptosis. 1531 17

The incidence of prostate cancer increases dramatically with age and the mechanism underlying this association is unclear. Age-dependent methylation of estrogen receptor alpha (ESR1) gene has been previously implicated in other cancerous and benign diseases. We evaluated the age-dependent methylation of ESR1 in prostate cancer. The methylation status of ESR1 in 83 prostate cancer samples from patients aged 49 to 77 years (mean age at 67.4 years) was examined using the bisulfite genomic sequencing technique. The samples were divided into three age groups: men aged 60 years and under (n = 14), men aged 61-70 years (n = 40), and men aged over 70 years (n = 29). Overall, ESR1 promoter methylation was detected in 54 out of 83 (65.1%) prostate samples. The methylation rate of ESR1 increased dramatically with age from 50.0% in patients aged 60 years and under to 89.7% for patients aged 70 years and over. Logistic regression analyses revealed that age and Gleason score were the only variables that affect incidence of ESR1 methylation; other clinical factors such as prostate-specific antigen level and clinical stage did not. We also calculated ESR1 methylation density (the percentage of methylated CpGs among all CpGs within the analyzed region) and severity (the percentage of methylated CpG alleles) for each sample analyzed. Multiple regression analyses showed a positive correlation between age and methylation density (beta, 0.35; P, 0.012; 95% CI, 0.26-2.01); while Gleason score was positively associated with methylation severity (beta, 0.45; P, 0.018; 95% CI, 1.04-4.26). These findings suggest that methylation of ESR1 is both age-dependent and tumor differentiation-dependent and age-dependent methylation of ESR1 may represent a mechanism linking aging and prostate cancer.
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PMID:Age-dependent methylation of ESR1 gene in prostate cancer. 1535 97

Estrogens have previously been extensively used in prostate cancer treatment. Serious side effects, primarily in cardiovascular system have, however, limited their use. The therapeutic effect of estrogen in preventing prostate cancer growth was mainly obtained indirectly by feedback inhibition of the hypothalamic release of LRH leading to lowered serum androgen levels and castration like effects. Prostate tissue is also most probably a target for direct regulation by estrogens. Prostate contains estrogen receptor alpha (ERalpha) and beta (ERbeta), which are localized characteristically in stroma and epithelium, respectively. The physiological function of these receptors is not known but there is evidence of the role of estrogens in prostatic carcinogenesis. Developing prostate seems particularly sensitive to increased level of endogenous and/or exogenous estrogens. Perinatal or neonatal exposure of rats and mice to estrogens leads to "imprinting" of prostate associated with increased proliferation, inflammation and dysplastic epithelial changes later in life. Prolonged treatment of adult rodents with estrogens along with androgens also leads to epithelial metaplasia, PIN-like lesions and even adenocarcinoma of prostate speaking for the role of estrogen in prostate cancer development. Recent results concerning antiestrogen inhibition of prostate cancer development beyond PIN-type lesions in transgenic mouse models further suggests a role for estrogens in prostate cancer progression. These results also suggest that direct inhibition of estrogen action at the level of prostate tissue may provide an important novel principle of development of prostate cancer therapies.
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PMID:Role of estrogens in development of prostate cancer. 1566 93

Surgical ovariectomy and orchiectomy, first proposed over a century ago, are effective in breast and prostate cancer therapy, respectively. Later, the discovery of steroid hormones and their nuclear receptors led to the concept that inhibition of steroid receptor function by an antagonist prevents tumour growth. While the first anti-hormones, cyproteroneacetate (CPA) and tamoxifen were found accidentally, deeper understanding of nuclear receptors as transcription factors enabled more rational, structure-activity based drug discovery. Results from a drug-finding program on pure anti-estrogens will be reported. These new steroidal anti-estrogens are highly active, pure ER-antagonists that lead to an efficient degradation of the estrogen receptor alpha (ERalpha) protein without any agonistic activity. Data obtained in preclinical tumour models in mice and rats showed a high potency in growth inhibition of ERalpha-positive breast cancer. In parallel, by comparing three independently generated anti-estrogen-resistant breast cancer cell lines, it was our intention to gain insight into the mechanisms of endocrine resistance which will allow to define new approaches for the treatment of endocrine-resistant breast cancer. Candidate proteins potentially involved in mechanisms of anti-estrogen-resistant growth of breast cancer cell lines were analyzed. ERalpha and progesterone receptor (PR) expressions were lost on the protein level in all three anti-estrogen-resistant cell lines, whereas binding of epidermal growth factor (EGF) and protein expression of epidermal growth factor receptor (EGFR) were increased. Loss of ERalpha expression may be linked to the acquisition of anti-estrogen resistance and enhanced expression of the EGFR and of members of the S100 family of Ca2+-binding proteins may contribute to the outgrowth of resistant cells. Furthermore, we describe the pharmacological development of a novel, highly potent progesterone receptor antagonist. In rat mammary tumour models, treatment with the PR antagonist completely suppressed the growth of established tumours and prevented the development of breast tumours. Advanced prostate cancer is effectively treated by androgen ablation. However, this therapy becomes inefficient although the androgen receptor (AR) is still functionally expressed. One novel strategy for the treatment of advanced prostate cancer could be the selective inhibition of AR protein expression by anti-sense oligonucleotides or small interfering RNA (siRNA) molecules. Down-regulation of the human AR caused significant inhibition of LNCaP prostate cancer growth in vivo. Taken together, many promising alternatives for endocrine therapy of breast and prostate cancer are arising.
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PMID:Steroid hormone receptors as targets for the therapy of breast and prostate cancer--recent advances, mechanisms of resistance, and new approaches. 1586 Feb 62


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