Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TP73 gene encodes a nuclear protein that has high homology with TP53. TP73 is rarely mutated in human cancer. The presence of a 1-kb regulatory fragment within the first intron of TP73 was recently reported. This fragment exerts silencer activity on TP73 mediated by ZEB. We searched for possible mutations in this negative regulatory region in 45 colorectal and 43 breast cancer patients and in 34 healthy donors. The study was carried out using the SSCP method, and the allelic variants detected were sequenced. The expression of TP73 was analyzed by quantitative RT-PCR, and loss of heterozygosity (LOH) was assessed by microsatellite study. In several samples, we identified an allele variant that corresponds to a deletion of 73 bp in tumor tissues and normal counterparts, localized between -489 and -417 from the ATG start site of exon 2. Among the 88 tumor samples, 35 (40%) showed at least 1 allele with the cited deletion, versus 7 of the 34 (21%) healthy donors (P = 0.045). When we classified the patients according to the number of variations into homozygous or heterozygous groups, the significance was clearer (P = 0.03). No LOH was detected in the heterozygous cases. There was a positive quantitative correlation between the expression of TP73 and the presence of the allelic variant (P = 0.029). These data suggest that this allelic variant is common in breast and colorectal cancers and that it could alter the expression of the TP73 gene with an additive effect.
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PMID:Intronic deletion affecting a negative regulatory region of TP73 is related to breast and colorectal carcinomas. 1473 27

The transcription factor nuclear factor kappa B (NF-kappaB) is constitutively active in both cancer cells and stromal cells of breast cancer; however, the precise role of activated NF-kappaB in cancer progression is not known. Using parental MCF10A cells and a variant that expresses the myoepithelial marker p63 stably overexpressing the constitutively active p65 subunit of NF-kappaB (MCF10A/p65), we show that NF-kappaB suppresses the expression of epithelial specific genes E-cadherin and desmoplakin and induces the expression of the mesenchymal specific gene vimentin. P65 also suppressed the expression of p63 and the putative breast epithelial progenitor marker cytokeratin 5/6. MCF10A/p65 cells were phenotypically similar to cells undergoing epithelial to mesenchymal transition (EMT). MCF10A/p65 cells failed to form characteristic acini in three-dimensional Matrigel. Analysis of parental and MCF10A/p65 cells for genes previously shown to be involved in EMT revealed elevated expression of ZEB-1 and ZEB-2 in MCF10A/p65 cells compared to parental cells. In transient transfection assays, p65 increased ZEB-1 promoter activity. Furthermore, MCF10A cells overexpressing ZEB-1 showed reduced E-cadherin and p63 expression and displayed an EMT phenotype. The siRNA against ZEB-1 or ZEB-2 reduced the number of viable MCF10A/p65 but not parental cells, suggesting the dependence of MCF10A/p65 cells to ZEB-1 and ZEB-2 for cell cycle progression or survival. MCF10A cells chronically exposed to tumor necrosis factor alpha (TNFalpha), a potent NF-kappaB inducer, also exhibited the EMT-like phenotype and ZEB-1/ZEB-2 induction, both of which were reversed following TNFalpha withdrawal.
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PMID:NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. 1686 83

Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell-cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour-host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.
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PMID:The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. 1748 63

MicroRNAs are approximately 22-nucleotide sequences thought to interact with multiple mRNAs resulting in either translational repression or degradation. We previously reported that several microRNAs had variable expression in mammalian cell lines, and we examined one, miR-200c, in more detail. A combination of bioinformatics and quantitative reverse transcription-PCR was used to identify potential targets and revealed that the zinc finger transcription factor transcription factor 8 (TCF8; also termed ZEB1, deltaEF1, Nil-2-alpha) had inversely proportional expression levels to miR-200c. Knockout experiments using anti-microRNA oligonucleotides increased TCF8 levels but with nonspecific effects. Therefore, to investigate target predictions, we overexpressed miR-200c in select cells lines. Ordinarily, the expression level of miR-200c in non-small-cell lung cancer A549 cells is low in contrast to normal human bronchial epithelial cells. Stable overexpression of miR-200c in A549 cells results in a loss of TCF8, an increase in expression of its regulatory target, E-cadherin, and altered cell morphology. In MCF7 (estrogen receptor-positive breast cancer) cells, there is endogenous expression of miR-200c and E-cadherin but TCF8 is absent. Conversely, MDA-MB-231 (estrogen receptor-negative) cells lack detectable miR-200c and E-cadherin (the latter reportedly due to promoter region methylation) but express TCF8. The ectopic expression of miR-200c in this cell line also reduced levels of TCF8, restored E-cadherin expression, and altered cell morphology. Because the down-regulation of E-cadherin is a crucial event in epithelial-to-mesenchymal transition, loss of miR-200c expression could play a significant role in the initiation of an invasive phenotype, and, equally, miR-200c overexpression holds potential for its reversal.
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PMID:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. 1780 4

The cysteine-rich protein CCN6 [or Wnt-1-induced signaling protein 3 (WISP3)] exerts tumor-suppressive effects in aggressive inflammatory breast cancer. Loss of CCN6 is associated with poorly differentiated phenotypes and increased invasion. Here, we show that reduction of CCN6 expression occurs in 60% of invasive breast carcinomas and is associated with axillary lymph node metastases. Furthermore, low CCN6 expression in invasive carcinoma tissue samples correlates with reduced expression of E-cadherin. In vitro, RNA interference knockdown of CCN6 in two benign human mammary epithelial cell lines (HME and MCF10A) decreased expression of E-cadherin protein and mRNA and reduced activity of the E-cadherin promoter; this reduction was dependent on intact E-box elements. CCN6 knockdown in HME cells resulted in up-regulation of the E-cadherin transcriptional repressors Snail and ZEB1 and enhanced their recruitment and binding to the E-cadherin promoter as analyzed by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail blocked the down-regulation of E-cadherin caused by CCN6 inhibition. These data show, for the first time, that CCN6 expression is reduced or lost in a substantial number of invasive breast carcinomas and that CCN6 modulates transcriptional repressors of E-cadherin. Together, our results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer.
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PMID:Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. 1832 96

Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) and miR-205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)-beta or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR-200 family alone was sufficient to prevent TGF-beta-induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 (also known as deltaEF1) and SIP1 (also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition (MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR-200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.
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PMID:The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. 1932 6

Epithelial-to-mesenchymal transition (EMT) is defined as phenotypic change of epithelial cells into mesenchymal cells. EMT, allowing cellular dissociation from epithelial tissues, plays a key role in invasion and metastasis during carcinogenesis as well as in gastrulation and neurulation during embryogenesis. SNAI1/Snail, SNAI2/Slug, ZEB1/deltaEF1/ZFHX1A, ZEB2/SIP1/ZFHX1B, TWIST1/TWIST, and TWIST2/DERMO1 are representative EMT regulators. ZEB2 represses transcription of CDH1, CLDN4, CCND1, TERT, SFRP1, ALPL and miR-200b-200a-429 primary miRNA, and upregulates transcription of mesenchymal markers. ZEB2 is relatively highly expressed in brain corpus callosum and monocytes. ZEB2 is expressed in various types of human tumors, such as breast cancer, gastric cancer, and pancreatic cancer. TGFbeta, TNFalpha, IL1, AKT and hypoxia signals are involved in ZEB2 upregulation and EMT induction; however precise mechanisms of ZEB2 transcription remained unclear. Here, refined integrative genomic analyses of ZEB2 gene were carried out. ZEB2 was co-expressed with POU3F2 (BRN2) and POU3F3 (BRN1) in brain corpus callosum, spinal cord, and fetal brain, whereas ZEB2 was co-expressed with POU2F2 (OCT2) in monocytes. Ets-Smad-binding CGGAGAC motif, bHLH-binding site, and POU/OCT-binding site within proximal promoter region, and NF-kappaB-binding site within intron 2 were completely conserved in human ZEB2, chimpanzee ZEB2, cow ZEB2, mouse Zeb2, rat Zeb2, and chicken zeb2 genes. In addition, HIF1alpha-binding site within proximal promoter region was conserved in mammalian ZEB2 orthologs. Consensus binding site for Hedgehog effector GLI was not identified within or adjacent to the 7-kb regions of human ZEB2 gene. TGFbeta, TNFalpha, IL1, and hypoxia signals directly upregulate ZEB2 to induce EMT, growth arrest, and senescence, whereas Hedgehog signals indirectly upregulate ZEB2 via TGFbeta. Together these facts indicate that ZEB2, occupying the crossroads of inflammation, aging and carcinogenesis, is an important target for drug discovery.
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PMID:Integrative genomic analyses of ZEB2: Transcriptional regulation of ZEB2 based on SMADs, ETS1, HIF1alpha, POU/OCT, and NF-kappaB. 1942 92

Epithelial-to-mesenchymal transition (EMT) plays an important role during normal embryogenesis, and it has been implicated in cancer invasion and metastasis. Here, we report that Ladybird homeobox 1 (LBX1), a developmentally regulated homeobox gene, directs expression of the known EMT inducers ZEB1, ZEB2, Snail1, and transforming growth factor beta2 (TGFB2). In mammary epithelial cells, overexpression of LBX1 leads to morphological transformation, expression of mesenchymal markers, enhanced cell migration, increased CD44(high)/CD24(low) progenitor cell population, and tumorigenic cooperation with known oncogenes. In human breast cancer, LBX1 is up-regulated in the unfavorable estrogen receptor (ER)/progesterone (PR)/HER2 triple-negative basal-like subtype. Thus, aberrant expression of LBX1 may lead to the activation of a developmentally regulated EMT pathway in human breast cancer.
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PMID:A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. 1965 85

The conversion of early stage tumors into invasive malignancies with an aggressive phenotype has been associated with the irreversible loss of E-cadherin expression. The loss of E-cadherin expression in human tumors, including breast cancer, has been attributed to promoter CpG island hypermethylation and direct inhibition by transcriptional repressors. Recent evidence demonstrates that up-regulation of E-cadherin by microRNA-200b (miR-200b) and miR-200c through direct targeting of transcriptional repressors of E-cadherin, ZEB1, and ZEB2, inhibits epithelial-to-mesenchymal transition (EMT), a crucial process in the tumor progression. We demonstrate that microRNA miR-200 family-mediated transcriptional up-regulation of E-cadherin in mesenchymal MDA-MB-231 and BT-549 cells is associated directly with translational repression of ZEB1 and indirectly with increased acetylation of histone H3 at the E-cadherin promoter. The increase in histone H3 acetylation may be attributed to the disruption of repressive complexes between ZEB1 and histone deacetylases and to the inhibition of SIRT1, a class III histone deacetylase. These events inhibit EMT and reactivate a less aggressive epithelial phenotype in cancer cells. Additionally, disruption of ZEB1-histone deacetylase repressor complexes and down-regulation of SIRT1 histone deacetylase up-regulate proapoptotic genes in the p53 apoptotic pathway resulting in the increased sensitivity of cancer cells to the chemotherapeutic agent doxorubicin.
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PMID:E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. 1983 49

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
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PMID:Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. 1986 Jun 66


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