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

The AP-2 transcription factors are required for normal growth and morphogenesis during mammalian development. Previous in vitro studies have also indicated that the AP-2 family of proteins may be involved in the etiology of human breast cancer. The AP-2 genes are expressed in many human breast cancer cell lines, and critical AP-2-binding sites are present in both the ERBB-2 (HER2/neu) and estrogen receptor promoters. We have now characterized immunological reagents that enable specific AP-2 family members, including AP-2alpha and AP-2gamma, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2alpha and AP-2gamma are both present in benign breast epithelia, there is a significant up-regulation of AP-2gamma expression in breast cancer specimens (P = 0.01). There was also a significant correlation between the presence of the AP-2alpha protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2alpha/AP-2gamma proteins and ERBB-2 expression (P = 0.003). Furthermore, we detected an association (P = 0.04) between the expression of AP-2gamma and the presence of an additional signal transduction molecule implicated in breast cancer, the insulin-like growth factor I receptor. Analysis of the proximal promoter of the insulin-like growth factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Taken together, these data strongly support a role for the AP-2 gene family in the control of cell growth and differentiation in breast cancer.
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PMID:Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. 985 80

The DNA repair enzyme, N-methylpurine DNA glyclosylase (MPG), is overexpressed in breast cancer as compared with its expression in normal breast epithelial cells. In an effort to determine the mechanism responsible for this difference in expression, we studied rates and regulation of transcription of the MPG gene in normal (HMEC), spontaneously immortalized (MCF10A), and malignant (T47D) mammary epithelial cells. Steady state levels of MPG mRNA are 3-4-fold greater in T47D cells than in MCF10A cells. Nuclear "run-off" transcription measurements revealed MPG transcription rates to be approximately 3-fold greater in the tumor cells than in normal cells. Characterization of the MPG promoter by deletion analysis and transient transfection experiments revealed that all basal promoter activity resided between nucleotides -227 and -81 upstream from the ATG translation start site. Constructs containing this region were expressed at 4-fold greater levels when transfected into malignant T47D cells (56 x baseline) than in MCF10A cells (14 x baseline). Computer database analysis of the region of nucleotides -227 to -81 revealed multiple overlapping Sp1 consensus binding sites and two overlapping consensus AP-2 binding sites located between bases -181 and -169. Electrophoretic mobility shift assays indicated that while Sp1 bound this region of the promoter, nuclear extracts from both cell types contained equal Sp1 binding activity. In contrast, AP-2 binding activity was significantly greater in T47D cells, and Western blots confirmed increased AP-2 protein levels in these cells. Cotransfection into MCF10A cells of the MPG promoter construct and an AP-2 expression plasmid increased MPG promoter activity 2.1-fold. Cotransfection of a dominant negative mutant of AP-2 into T47D cells reduced the extent of MPG promoter-driven transcription by 50%. To investigate the functional significance of the two overlapping AP-2 consensus binding sites, each site was mutated separately. Mutation of the upstream site decreased promoter activity by 15%, but mutation of the downstream site decreased promoter activity by 45% and abolished AP-2 binding to the promoter sequence. These data suggest that AP-2 is important in regulating MPG expression in breast cancer cells, and that the increased amount of AP-2 in these cells plays a major role in directing the increased expression of MPG.
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PMID:Regulation of expression of N-methylpurine DNA glycosylase in human mammary epithelial cells: role of transcription factor AP-2. 1056 36

The UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 (Gal NAc-T3) gene, a member of the Gal NAc transferase gene family, is expressed in a tissue-specific manner. To elucidate the function of this gene, we have focused on the molecular mechanism underlying regulation of gene expression. We have cloned Gal NAc-T3 cDNA and used it to show that Gal NAc-T3 mRNA is expressed in tumor cell lines derived from secretory epithelial tissue adenocarcinomas but not in cell lines derived from bladder and epidermoid carcinomas. Using a polyclonal antibody to Gal NAc-T3, we observed protein expression in adenocarcinoma but not non-adenocarcinoma cell lines, and in breast carcinoma cells but not in normal breast tissue. We used Gal NAc-T3 cDNA to isolate three overlapping genomic clones containing the 5'-portion of the human Gal NAc-T3 gene, and we sequenced 1.6 kb around the first exon. A transient expression assay using the luciferase gene showed that promoter activity was much higher in MCF-7 cells than in KB cells. In vivo footprint experiments showed significant protection of a distal GC box, an NRF-1 site, and an AP-2 site in MCF-7 cells. A novel stem and loop structure extending from nucleotide -103 to nucleotide -165 and contiguous to these transcription factor binding sites seemed to be functional in regulating Gal NAc-T3 gene transcription, and a KMnO4 footprint experiment showed that this stem and loop structure could be formed in vivo. We also observed dimethyl sulfate hypersensitive sites in the untranslated region around nucleotide +50 in MCF-7 but not in KB cells. These findings indicate that Gal NAc-T3 gene expression is regulated by multiple systems, including transcription factor binding sites and a stem-and-loop structure, and that this regulation is restricted to cell lines derived from epithelial gland adenocarcinomas but not cells derived from nonsecretory epithelial tissue carcinomas. In addition, our immunohistochemical results suggest that our anti-Gal NAc-T3 antibody may be useful for diagnostic purposes in the early stages of breast cancer.
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PMID:Structural basis for the regulation of UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 gene expression in adenocarcinoma cells. 1062 15

This paper describes the generation and characterization of a monoclonal antibody specific for two members of the AP-2 family of transcription factors, AP-2alpha and AP-2beta, and its subsequent application to archival primary breast tumour material. Nuclear localization of AP-2 was found in all expressing cases, but in general levels of immunostaining were low, with only 17 per cent of the 86 tumours examined showing very high expression levels. Nevertheless, data analysis of the whole patient series allowed the identification of significant relationships between levels of AP-2 and other important breast markers. Thus, expression of AP-2alpha/beta was found to correlate significantly with expression of both ER ( p=0.036*) and the universal cell-cycle inhibitor p21(cip) ( p=0.03*), but was inversely related to levels of the proto-oncogene ErbB2 ( p=0.008*). AP-2-positive tumours also showed a low rate of proliferation, with significantly reduced mitotic count and a lower tumour grade. There was no significant relationship with clinical parameters, but samples with adjacent normal tissue indicated that loss of the AP-2 marker was associated with disease progression from normal breast through to invasive disease. This was confirmed by examining separate series of pure normal and pure DCIS samples, both of which expressed significantly higher levels of AP-2 ( p=0.0001* in each case) than the invasive tumours. Overall, these findings implicate AP-2alpha/beta as having a role akin to that of a tumour suppressor in breast cancer.
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PMID:Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer. 1062 51

Transcription of the ERBB2 oncogene is repressed by oestrogen in human breast cancer cells. We show that a 218 bp fragment of the human ERBB2 gene promoter is responsive to oestrogen in transient transfection in ZR75.1 and SKBR.3 cells when the oestrogen receptor is expressed. Deletion analysis of this fragment shows that a sequence located at the 5' end, which is known to mediate ERBB2 overexpression in breast cancer, is also responsible for the oestrogen response. This sequence binds AP-2 transcription factors and appears functionally identical to an element of the oestrogen-dependent enhancer described in the first intron of human ERBB2. We observed that oestrogen treatment down-regulates expression of AP-2 proteins but does not affect the DNA binding activity of AP-2. Constitutive expression of AP-2beta or AP-2gamma, but not AP-2alpha, abrogates the estrogenic repression. Our results demonstrate that AP-2 transcription factors are implicated in the oestrogenic regulation of ERBB2 gene expression and suggest a complex interplay involving the different AP-2 isoforms and other unidentified factors.
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PMID:AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen. 1064 7

To gain insight into the molecular regulation of the human vitamin D3 receptor (hVDR), we have cloned and sequenced the 5' flanking region of exon 1c and examined promoter activity of this region in breast cancer cells. Sequence analysis of the first 1300 bp upstream of exon 1c reveals several characteristics of a class II promoter, including GC-rich regions and the presence of a TATA box at -29 bp. Putative transcription factor binding sites identified in this potential hVDR promoter include AP-2, Sp-1, and glucocorticoid response elements. No consensus vitamin D3 (VDRE) or estrogen (ERE) responsive elements were identified in the promoter sequence. Primer extension analysis performed with a primer specific for exon 1c confirms that transcription initiated in the 5' flanking region of exon 1c occurs in MCF-7 cells. Transient transfection of MCF-7 cells with this putative promoter region cloned into the pRLnull luciferase reporter vector generates significant reporter gene activity that is enhanced by treatment with forskolin, retinoic acid, and 17beta-estradiol. The enhancement of exon 1c promoter activity by 17beta-estradiol is blocked by the selective estrogen response modifier (SERM) tamoxifen and is not observed in estrogen receptor-negative breast cancer cells. In summary, we have cloned and characterized a TATA containing promoter upstream of exon 1c of the hVDR and provide evidence that this region represents a hormonally regulated hVDR promoter.
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PMID:Identification of a hormone-responsive promoter immediately upstream of exon 1c in the human vitamin D receptor gene. 1091 69

Several reports have linked activating protein 2alpha (AP-2alpha) to apoptosis, leading us to hypothesize that AP-2alpha is a substrate for caspases. We tested this hypothesis by examining the effects of tumor necrosis factor alpha (TNF-alpha) on the expression of AP-2 in breast cancer cells. Here, we provide evidence that TNF-alpha downregulates AP-2alpha and AP-2gamma expression posttranscriptionally during TNF-alpha-induced apoptosis. Both a general caspase antagonist (zVADfmk) and a caspase 6-preferred antagonist (zVEIDfmk) inhibited TNF-alpha-induced apoptosis and AP-2alpha downregulation. In vivo tests showed that AP-2alpha was cleaved by caspases ahead of the DNA fragmentation phase of apoptosis. Recombinant caspase 6 cleaved AP-2alpha preferentially, although caspases 1 and 3 also cleaved it, albeit at 50-fold or higher concentrations. Activated caspase 6 was detected in TNF-alpha-treated cells, thus confirming its involvement in AP-2alpha cleavage. All three caspases cleaved AP-2alpha at asp(19) of the sequence asp-arg-his-asp (DRHD(19)). Mutating D(19) to A(19) abrogated AP-2alpha cleavage by all three caspases. TNF-alpha-induced cleavage of AP-2alpha in vivo led to AP-2alpha degradation and loss of DNA-binding activity, both of which were prevented by pretreatment with zVEIDfmk. AP-2alpha degradation but not cleavage was inhibited in vivo by PS-431 (a proteasome antagonist), suggesting that AP-2alpha is degraded subsequent to cleavage by caspase 6 or caspase 6-like enzymes. Cells transfected with green fluorescent protein-tagged mutant AP-2alpha are resistant to TNF-alpha-induced apoptosis, further demonstrating the link between caspase-mediated cleavage of AP-2alpha and apoptosis. This is the first report to demonstrate that degradation of AP-2alpha is a critical event in TNF-alpha-induced apoptosis. Since the DRHD sequence in vertebrate AP-2 is widely conserved, its cleavage by caspases may represent an important mechanism for regulating cell survival, proliferation, differentiation, and apoptosis.
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PMID:Transcription factor AP-2alpha is preferentially cleaved by caspase 6 and degraded by proteasome during tumor necrosis factor alpha-induced apoptosis in breast cancer cells. 1143 43

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed.
Breast Cancer Res 2001
PMID:Update on HER-2 as a target for cancer therapy: the ERBB2 promoter and its exploitation for cancer treatment. 1173 92

ErbB-3 (HER3) is a member of the epidermal growth factor receptor family. Increasing evidence suggests that elevated expression of ErbB-3 is important for malignancy. In this study, we found that elevated levels of ErbB-3 expression did not occur in the absence of AP-2gamma in a panel of human mammary epithelial and fibroblasts cell lines. In contrast, there was no association between the expression of AP-2alpha or AP-2beta and the level of ErbB-3, or between AP-2alpha and AP-2gamma double positivity and ErbB-3 expression. In co-transfection experiments, exogenous expression of AP-2gamma robustly activated ErbB-3 promoter activity. Moreover, expression of a dominant negative AP-2 protein, AP-2delta (deleted residues 31-117), not only repressed the ErbB-3 promoter activity but also suppressed endogenous ErbB-3 transcription in the ErbB-3 overexpressing cell line MRC-5VA. Overexpression of AP-2A resulted in a decreased proliferation rate and inhibitin of colony formation. Taken together, these data strongly support a role for the AP-2 gene family, in particular, AP-2gamma, in the control of ErbB-3 expression. Interference with the function of transcription factor AP-2 might provide a potential strategy for modulation of the malignant phenotype.
Breast Cancer Res Treat 2002 Jan
PMID:Dominant negative interference of transcription factor AP-2 causes inhibition of ErbB-3 expression and suppresses malignant cell growth. 1185 73

The members of the AP-2 family of transcription factors play important roles during mammalian development and morphogenesis. AP-2gamma (Tcfap2c - Mouse Genome Informatics) is a retinoic acid-responsive gene implicated in placental development and the progression of human breast cancer. We show that AP-2gamma is present in all cells of preimplantation embryos and becomes restricted to the extra-embryonic lineages at the time of implantation. To study further the biological function of AP-2gamma, we have generated Tcfap2c-deficient mice by gene disruption. The majority of Tcfap2c(-/-) mice failed to survive beyond 8.5 days post coitum (d.p.c.). At 7.5 d.p.c., Tcfap2c(-/-) mutants were typically arrested or retarded in their embryonic development in comparison to controls. Morphological and molecular analyses of mutants revealed that gastrulation could be initiated and that anterior-posterior patterning of the epiblast remained intact. However, the Tcfap2c mutants failed to establish a normal maternal-embryonic interface, and the extra-embryonic tissues were malformed. Moreover, the trophoblast-specific expression of eomesodermin and Cdx2, two genes implicated in FGF-responsive trophoblast stem cell maintenance, was significantly reduced. Chimera studies demonstrated that AP-2gamma plays no major autonomous role in the development of the embryo proper. By contrast, the presence of AP-2gamma in the extra-embryonic membranes is required for normal development of this compartment and also for survival of the mouse embryo.
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PMID:Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development. 1201


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