UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of total estrogen receptor beta (ERbeta) expression has been implicated in breast tumorigenesis. The ERbeta gene yields five exon 8 alternatively spliced transcripts (ERbeta1-5), which encode proteins with different C-terminal amino acids. Individual expression analysis of these transcripts may provide new insights into estrogen signaling in breast cancer. We measured mRNA levels of total ERbeta and its five isoforms in normal tissues, breast carcinomas from post-menopausal patients, and breast cancer cell lines by means of real-time reverse transcription-polymerase chain reaction and fluorescent fragment analysis. In various normal human tissues, ERbeta1-5 isoforms displayed different qualitative and quantitative expression patterns that were consistent with previous reports. Total ERbeta mRNA levels were significantly lower in breast tumors than in normal breast tissues (38-fold lower, P < 0.001), mainly due to lower expression of ERbeta1 and ERbeta2 (ERbeta5 expression was similar in the two tissue types). This altered expression pattern of ERbeta isoforms in breast cancer should be taken into account in future ERbeta-based clinical applications.
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PMID:Altered expression pattern of alternatively spliced estrogen receptor beta transcripts in breast carcinoma. 1537 39

Deregulated expression of the Wilms' tumor gene (WT1) has been implicated in the maintenance of a malignant phenotype in leukemias and a wide range of solid tumors through interference with normal signaling in differentiation and apoptotic pathways. Expression of high levels of WT1 is associated with poor prognosis in leukemias and breast cancer. Using real-time (Taqman) reverse transcription-PCR and RNase protection assay, we have shown up-regulation of WT1 expression following cytotoxic treatment of cells exhibiting drug resistance, a phenomenon not seen in sensitive cells. WT1 is subject to alternative splicing involving exon 5 and three amino acids (KTS) at the end of exon 9, producing four major isoforms. Exon 5 splicing was disrupted in all cell lines studied following a cytotoxic insult probably due to increased exon 5 skipping. Disruption of exon 5 splicing may be a proapoptotic signal because specific targeting of WT1 exon 5-containing transcripts using a nuclease-resistant antisense oligonucleotide (ASO) killed HL60 leukemia cells, which were resistant to an ASO targeting all four alternatively spliced transcripts simultaneously. K562 cells were sensitive to both target-specific ASOs. Gene expression profiling following treatment with WT1 exon 5-targeted antisense showed up-regulation of the known WT1 target gene, thrombospondin 1, in HL60 cells, which correlated with cell death. In addition, novel potential WT1 target genes were identified in each cell line. These studies highlight a new layer of complexity in the regulation and function of the WT1 gene product and suggest that antisense directed to WT1 exon 5 might have therapeutic potential.
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PMID:Disruption of WT1 gene expression and exon 5 splicing following cytotoxic drug treatment: antisense down-regulation of exon 5 alters target gene expression and inhibits cell survival. 1554 86

A breast cancer cell line developed in our laboratory (SUM-52PE) has a 12-fold amplification and high-level overexpression of the oncogene fibroblast growth factor receptor 2 (FGFR2). Previously, nine different alternatively spliced FGFR2 variants were isolated from this cell line. Overexpression of two variants that differ only in their carboxyl termini (C1 and C3) has been successfully accomplished in the immortalized human mammary epithelial cell line H16N2. FGFR2 expression led to the activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling cascades. Phosphorylation of the adapter protein FGF receptor substrate 2 is much more robust in the cells expressing the C3 variant of FGFR2 compared with the C1 variant. H16N2 cells expressing the full-length FGFR2 with the C1 or C3 carboxyl terminus were tested for their ability to grow under epidermal growth factor (EGF)-independent conditions, in soft agar, and for their ability to invade naturally occurring basement membranes and compared with the parental SUM-52PE cell line. All three cell lines grew under EGF-independent conditions and all were inhibited by the FGFR family specific inhibitor PD173074. The full-length FGFR2-C1 and FGFR2-C3 variants grew robustly in soft agar similar to the parental cell line SUM-52PE. However, cells expressing the C3 variant formed large colonies in agar in both insulin-free and EGF-free medium, whereas the cells expressing the C1 variant required insulin for growth. Soft agar growth was also inhibited by PD173074. Because SUM-52PE was developed from a metastatic breast carcinoma, the FGFR2-overexpressing cell lines were assessed for their ability to invade sea urchin embryo cell membranes. H16N2 cells expressing the C1 carboxyl terminus failed to invade sea urchin embryo cell membranes. By contrast, FGFR2-C3-expressing cells were as invasive as the SUM-52 breast cancer cells and erbB-2-overexpressing H16N2 cells. These results indicate that FGFR2 is a transforming oncogene in human mammary epithelial cells when expressed to levels similar to that found in breast cancer cells with FGFR2 gene amplification. Furthermore, the results suggest that different splice variants have differing transforming activities and that signaling from variants expressing the C3 carboxyl terminus results in more autonomous signaling, cell growth, and invasion.
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PMID:Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. 1556 80

BARD1 is a crucial partner of the breast and ovarian tumor suppressor BRCA1 required for ubiquitin ligase activity and for reciprocal stabilization in cells. We report here an alternatively spliced human BARD1 mRNA variant (BARD1DeltaRIN) isolated from a HeLa cell cDNA library. It is characterized by deletion of exons 2-6 that encode most of the RING finger domain and the entire span of ankyrin repeats. DeltaRIN transcript was detected in all breast cancer-cell lines studied although its protein expression level was low. DeltaRIN does not interact with BRCA1, whereas it interacts with and colocalizes with CstF-50 to cytoplasmic dots. Hence, a deletion variant of BARD1 occurs in cells and may play a distinct role with CstF-50.
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PMID:A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. 1587 32

The IGF-I receptor (IGF-IR) has an important role in breast cancer development and progression. Previous studies have suggested that the IGF-IR gene is negatively regulated by a number of transcription factors with tumor suppressor activity, including the Wilms' tumor protein WT1. The present study was aimed at evaluating the hypothesis that IGF-IR gene transcription in breast cancer cells is under inhibitory control by WT1 and, furthermore, that the mechanism of action of WT1 involves functional and physical interactions with estrogen receptor-alpha (ERalpha). Results of transient coexpression experiments showed that all four predominant isoforms of WT1 (including or lacking alternatively spliced exons 5 and 9) repressed IGF-IR promoter activity by 39-49%. To examine the potential interplay between WT1 and ERalpha in control of IGF-IR gene transcription we employed ER-depleted C4 cells that were generated by clonal selection of ER-positive MCF-7 cells that were maintained in estrogen-free conditions. IGF-IR levels in C4 cells were approximately 43% of the values in MCF-7 cells whereas WT1 levels in C4 cells were 4.25-fold higher than in MCF-7. Triple cotransfection experiments using an ERalpha expression vector in the absence or presence of WT1 expression vectors, along with an IGF-IR promoter reporter plasmid, revealed that ERalpha stimulated IGF-IR promoter activity whereas coexpression of WT1 abrogated the effect of ERalpha. In addition, co-immunoprecipitation experiments demonstrated a specific association between WT1 and ERalpha. Combined, our results suggest that WT1 suppresses IGF-IR gene transcription in breast cancer cells via a mechanism that involves protein-protein association with ERalpha. As a result of this interaction, the ability of ERalpha to transactivate the IGF-IR promoter is abrogated. These findings are consistent with a potential tumor suppressor role for WT1 in breast cancer and suggest that WT1 inactivation in tumoral cells may result in deregulated IGF-IR gene expression and enhanced mitogenic activation by locally produced and/or circulating IGFs.
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PMID:The WT1 Wilms' tumor suppressor gene product interacts with estrogen receptor-alpha and regulates IGF-I receptor gene transcription in breast cancer cells. 1608 27

The ErbB1 and ErbB2 receptors are oncogenes with therapeutic significance in human cancer, whereas the transforming potential of the related ErbB4 receptor has remained controversial. Here, we have addressed whether four alternatively spliced ErbB4 isoforms differ in regulating cellular responses relevant for tumor growth. We show that the two tumor necrosis factor-alpha converting enzyme (TACE)-cleavable ErbB4 isoforms (the juxtamembrane [JM]-a isoforms) were overexpressed in a subset of primary human breast cancers together with TACE. The overexpression of the JM-a cytoplasmic (CYT)-2 ErbB4 isoform promoted ErbB4 phosphorylation, survival of interleukin-3-dependent cells, and proliferation of breast cancer cells even in the absence of ligand stimulation, whereas activation of the other three ErbB4 isoforms required ligand stimulation. Ligand-independent cellular responses to ErbB4 JM-a CYT-2 overexpression were regulated by both tyrosine kinase activity and a two-step proteolytic generation of an intracellular receptor fragment involving first a TACE-like proteinase, followed by gamma-secretase activity. These data suggest a novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor.
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PMID:Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth. 1625 61

Survivin gene and its two alternatively spliced variants, survivin-2 B and survivin- Delta Ex3 gene were cloned from human breast cancer cell lines B-cap37 firstly. A new gene designated as survivin-image (SI) was cloned from above cell lines, which has not been reported yet to clone from any cell lines. It was found that the novel gene 507 bp comprises partial survivin gene (345 bp), partial image gene (155 bp) of eye cancer and other insertion of 7 bp by analyzing with a series of recent bioinformatics software at the level of nucleotide and protein deduced. Predicted 3-D structures of the new molecule showed greatly similar to that of survivin in N-terminal containing BIR by homology modeling. These results suggested SI gene (GenBank accession No.AY830084) might be a novel alternatively spliced isoforms of the survivin gene involved in other functional significances related to tumorigenesis.
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PMID:Molecular cloning and bioinformatics analysis of a novel spliced variant of survivin from human breast cancer cells. 1632 64

The estrogen receptor-alpha gene (ESR1) was previously identified as a direct target of the homeobox transcription factor BARX2 in MCF7 cells. Here, we show that BARX2 and ESR1 proteins bind to different ESR1 gene promoters and regulate the expression of alternatively spliced mRNAs that encode 66 and 46 kDa ESR1 protein isoforms. BARX2 increases the expression of both ESR1 isoforms; however, it has a greater effect on the 46 kDa isoform, leading to an increased ratio between the 46 and 66 kDa proteins. BARX2 also influences estrogen-dependent processes such as anchorage-independent growth and modulates the expression of the estrogen-responsive genes SOX5, RBM15, Dynein and Mortalin. In addition, BARX2 expression promotes cellular invasion and increases the expression of active matrix metalloproteinase-9 (MMP9). BARX2 also increases the expression of the tissue inhibitor of metalloproteinase (TIMP) genes, TIMP1 and TIMP3, in cooperation with estrogen signaling. Overall, these data indicate that BARX2 and ESR1 may coordinately regulate cell growth, survival and invasion pathways that are critical to breast cancer progression.
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PMID:BARX2 and estrogen receptor-alpha (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion. 1663 75

The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.
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PMID:A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. 1675 86

Metastasis tumor-associated 1 short form (MTA1s) is a naturally occurring, alternatively spliced variant of MTA1 that functions as a repressor of estrogen receptor (ER) alpha transcriptional functions, at least in part by binding and sequestering ERalpha in the cytoplasm. A unique C-terminal 33-amino acid region containing a nuclear receptor (NR)-box motif (-LRILL-) mediates binding of MTA1s with ERalpha and is indispensable in this interaction. Here, we elucidated the solution structure of this 33-amino acid region by NMR spectroscopy. We found a predominance of the alpha-helical region toward the N-terminal region, which includes the NR-box motif. In silico docking and comparison studies showed similarities between the NR-box motif of MTA1s and a similar motif of coregulators, both in structure and mode of ERalpha binding. In MCF-7 breast cancer cells, the MTA1s peptide effectively repressed ERalpha transactivation function, as evidenced by the estrogen response element-luc assay and down-regulation of estrogen-induced genes. In mechanistic studies, we found that the antiestrogenic effects of the MTA1s peptide were due to its ability to compete with the coactivator recruitment to ERalpha. Furthermore, the peptide efficiently repressed estrogen-induced proliferation and anchorage-independent growth of MCF-7 cells. In addition, the MTA1s peptide blocked the progression of tumors formed by MCF-7 cells overexpressing an ERalpha coactivator in a xenograft-based assay. In brief, the characterization of structure and antiestrogenic activity of MTA1s peptide highlight its therapeutic potential.
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PMID:Solution structure and antiestrogenic activity of the unique C-terminal, NR-box motif-containing region of MTA1s. 1680 47

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