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

Loss of heterozygosity at chromosome 8p21-22 is common in human prostate cancer, suggesting the presence of one or more tumor suppressor genes at this locus. A homeobox gene that is expressed specifically in adult human prostate, NKX3.1, the expression of which is regulated by androgen, maps to chromosome 8p21. Fine structure in situ mapping showed that NKX3.1 is proximal to MSR32 (macrophage scavenger receptor type II) and LPL (human lipoprotein lipase) and very close to NEFL (human neurofilament light chain) on 8p21. Single-strand conformational polymorphism analysis of 48 radical prostatectomy cancer specimens and 3 metastases for the entire coding region of NKX3.1 showed no tumor-specific sequence alterations in 50 specimens and total absence of the gene in 1 specimen known to have a biallelic deletion of 8p21. NKX3.1 was found to have a polymorphism at nucleotide 154 in codon 52 that resulted in a CGC-->TGC sequence change and an Arg-->Cys amino acid alteration (R52C). This polymorphism was present in 20% of DNA samples. If NKX3.1 is a target of the 8p21 LOH, it is not via disruption of the coding region of the gene.
 ...
PMID:Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. 937 51

NKX3.1 is a prostate-specific homeobox gene located on chromosome 8p21. In the mouse, Nkx3.1 has growth-suppressive and differentiating effects on prostatic epithelium. Mutations of the coding region of NKX3.1 were not found in human prostate cancer, failing to support the notion that NKX3.1 was a tumor suppressor gene. To study the expression o NKX3.1 protein in human tissues and prostate cancer, we derived a rabbit antiserum against purified recombinant NKX3.1. Among normal human tissues, NKX3.1 expression was seen in testis, in rare pulmonary mucous glands, and in isolated regions of transitional epithelium of the ureter. NKX3.1 was uniformly expressed in nuclei of normal prostate epithelial cells in 61 histological sections from radical prostatectomy specimens. We analyzed 507 samples of neoplastic prostate epithelium, most of which were contained on a tissue microarray that contained samples from different stages of prostatic neoplasia. We observed complete loss of NKX3.1 expression in 5% of benign prostatic hyperplasias, 20% of high-grade prostatic intraepithelial neoplasias, 6% of T1a/b samples, 22% of T3/4 samples, 34% of hormone-refractory prostate cancers, and 78% of metastases. Our data show that NKX3.1 expression is highly, but not exclusively, specific for the prostate. Loss of NKX3.1 expression is strongly associated with hormone-refractory disease and advanced tumor stage in prostate cancer (P < 0.0001).
 ...
PMID:Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. 1108 35

Chromosomal deletion appears to be the earliest as well as the most frequent somatic genetic alteration during carcinogenesis. It inactivates a tumor suppressor gene in three ways, that is, revealing a gene mutation through loss of heterozygosity as proposed in the two-hit theory, inducing haploinsufficiency through quantitative hemizygous deletion and associated loss of expression, and truncating a genome by homozygous deletion. Whereas the two-hit theory has guided the isolation of many tumor suppressor genes, the haploinsufficiency hypothesis seems to be also useful in identifying target genes of chromosomal deletions, especially for the deletions detected by comparative genomic hybridization (CGH). At present, a number of chromosomal regions have been identified for their frequent deletions in prostate cancer, including 2q13-q33, 5q14-q23, 6q16-q22, 7q22-q32, 8p21-p22, 9p21-p22, 10q23-q24, 12p12-13, 13q14-q21, 16q22-24, and 18q21-q24. Strong candidate genes have been identified for some of these regions, including NKX3.1 from 8p21, PTEN from 10q23, p27/Kip1 from 12p13, and KLF5 from 13q21. In addition to their location in a region with frequent deletion, there are functional and/or genetic evidence supporting the candidacy of these genes. Thus far PTEN is the most frequently mutated gene in prostate cancer, and KLF5 showed the most frequent hemizygous deletion and loss of expression. A tumor suppressor role has been demonstrated for NKX3.1, PTEN, and p27/Kip1 in knockout mice models. Such genes are important targets of investigation for the development of biomarkers and therapeutic regimens.
Cancer Metastasis Rev 2001
PMID:Chromosomal deletions and tumor suppressor genes in prostate cancer. 1208 61

The vast majority of invasive breast tumors are ductal and lobular breast carcinomas. Despite the many similarities, some clinical follow-up data and the patterns of metastases suggest that these histological subtypes of breast cancer are biologically distinct. Few papers, however, describe immunohistochemical markers useful for differentiation of these carcinomas. Many investigations suggest that E cadherin protein expression is lost in lobular but not in ductal carcinoma. The absence of E-CD, as a partial loss of epithelial differentiation, may account for the extended spread of lobular carcinoma in situ and the peculiar diffuse invasion mode of invasive lobular carcinoma. Some investigations report the significance of E-CD associated proteins alpha-, beta-, gamma-catenin expression, as well as the usefulness of cytokeratins 5, 6, 8, 7 and thrombospondin in differentiating histological types of breast invasive carcinomas. Several reports have suggested the possibility that invasive ductal and lobular cancers differ with respect to expression of antigens involved in proliferation and cell cycle regulation. It has been shown that vascular endothelial growth factor expression, also the expression of maspin, a tumour suppressor gene product, is higher in ductal, than in lobular carcinoma. Expression of NKX3.1, a member of the NK-class of homeodomain, is highly restricted and is found primarily in lobular carcinoma. Some histological and immunohistochemical characteristics of pleomorphic lobular carcinoma are also discussed.
 ...
PMID:Differentiation of tumours of ductal and lobular origin: I. Proteomics of invasive ductal and lobular breast carcinomas. 1617 Mar 89

Tumor suppressor function of ubiquitously expressed Annexin-A7, ANXA7 (10q21) that is involved in exocytosis and membrane fusion was based on cancer prone phenotype in Anxa7(+/-) mice as well as ANXA7 role in human prostate and breast cancers. To clarify ANXA7 biomarker and tumor suppressor function, we analyzed its expression pattern in comparison to the prostate-specific biomarker NKX3.1. Immunohistochemistry-based ANXA7 and NKX3.1 protein expression was analyzed on human tissue microarrays of 4,061 specimens from a wide spectrum of the histopathologically well-characterized tumors in different stages compared to corresponding normal tissues. Decreased ANXA7 expression was mostly associated with high invasive potential in multiple tumors. Although some metastases retained relatively high ANXA7 rates compared to primary cancer tissues, the lymph node metastases from different sites (including prostate and breast) had decreased ANXA7 expression in comparison to the intact lymphatic tissues. Major ANXA7 downregulation pattern was deviated in tumors of glandular (especially neuroendocrine) origin. ANXA7 and NKX3.1 proteins were synexpressed in the male urogenital system and adrenal gland. Gene expression profiling in prostate and breast cancers (SMD) revealed distinct hormone-related profiles for NKX3.1 and ANXA7, where ANXA7 expression correlated with steroid sulfatase which has a pivotal role in steroidogenesis. Abundant protein presence in adrenal gland and its loss in hormone-refractory prostate cancer indicated that ANXA7 can be relevant to steroidogenesis and androgen sensitivity in particular. With tumor suppressor pattern validated in different tumors, ANXA7 can be an attractive diagnostic and therapeutic target associated with the hormone and/or neurotransmitter-mediated modulation of tumorigenesis.
 ...
PMID:ANXA7 expression represents hormone-relevant tumor suppression in different cancers. 1770 71

A meta-analysis of recent data from the literature underscores the considerable body of present knowledge concerning prostate carcinogenesis, in part due to the numerous molecular biology tools now at our disposal. As concerns early events, much interest is being paid to modifications in the expression of GSTP1 and NKX3.1 occurring in totipotent stem cell populations. The discovery of fusion genes implicating TMPRSS2 and ERG (and, on rare occasions, other ETS family transcription factors) constitutes a major advance. Under physiological androgenic stimulation, the presence of these fusion genes leads to overexpression of genes involved in cell growth and differentiation. Concomitantly, alterations in numerous signalling pathways (growth factors, Wnt-beta catenine, PI3K/Akt) are responsible for the onset of an aggressive tumor phenotype. Hormono-independence is currently explained by an amplification of, or mutations in, androgenic receptors. These are facilitated by genomic instabilities linked to alterations in proteins which regulate gene expression, such as EZH2, and by the influence of the tumor microenvironment. Disturbances in the interactions between tumor cells and the microenvironment contribute to local extension of the tumor. Changes in the expression of E-cadherin are responsible for modifications in cell adhesion to the extracellular matrix. The expression of metalloproteases and of angiogenic factors favors tumor dissemination. Finally, the bone tropism in prostate metastases is probably linked to osteomimetic properties of prostate tumor cells which are capable of expressing certain proteins involved in bone remodelling, such as Runx-2, BSP (bone sialoprotein) and BMP (bone morphogenetic protein). Numerous studies remain to be carried out in order to correlate the identified genetic profiles and molecular anomalies with tumor prognosis. Nevertheless, the possibility of decrypting these anomalies for use in therapeutic applications is encouraging.
 ...
PMID:[Molecular aspects of prostate cancer: recent data from the literature]. 1784 97

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.
 ...
PMID:Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. 1787 89

The transforming growth factor beta, Hedgehog, Notch, and Wnt signaling pathways all play critical roles in the development and progression of prostate cancer. It is becoming increasingly apparent that these pathways may intersect with developmentally important transcription factors such as the sex-determining region Y-box 4 (SOX4), homeobox C6, enhancer of zeste 2, and ETS-related gene, which are up-regulated in prostate cancers. For example, identification of the downstream targets of SOX4 and homeobox C6 suggests that these factors may cooperate to activate the Notch pathway and the PI3K/AKT pathway, possibly in response to Wnt signals. PI3K/AKT activation likely occurs indirectly via up-regulation of growth factor receptors, while Notch activation is secondary to up-regulation of Notch pathway components. In addition, SOX4 may affect terminal differentiation via regulation of other transcription factors such as NKX3.1 and MLL, and regulation of components of the microRNA pathway such as Dicer and Argonaute 1. The evidence supporting activation of these pathways in prostate cancer progression suggests that combinations of compounds targeting them may be of benefit to patients with aggressive, metastatic disease.
 ...
PMID:The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. 2001 90

NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians' Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1 genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1 and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1 genotype does not modify the association between serum IGF-I levels and prostate cancer risk.
...
PMID:Variant NKX3.1 and Serum IGF-1: Investigation of Interaction in Prostate Cancer. 2438 13

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-na&iuml;ve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-na&iuml;ve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.
 ...
PMID:Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity. 2967


1 2 Next >>