Faculty Opinions recommendation of Dominant negative ATM mutations in breast cancer families.

2002 ◽  
Author(s):  
Alejandro Schaffer
Keyword(s):  
Breast Cancer ◽  
Dominant Negative

scholarly journals Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

2004 ◽  
Vol 15 (7) ◽  
pp. 3266-3284 ◽  
Author(s):  
Romaine Ingrid Fernando ◽  
Jay Wimalasena
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Dominant Negative ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro

2006 ◽  
Vol 133 (2) ◽  
pp. 83-92 ◽  
Author(s):  
Hui-Ming Dong ◽  
Gang Liu ◽  
Yi-Feng Hou ◽  
Jiong Wu ◽  
Jin-Song Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Inflammatory Breast Cancer ◽  
Breast Cancer Cells ◽  
Dominant Negative ◽  
E Cadherin

scholarly journals Loss of an Estrogen Receptor Isoform (ERαΔ3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

1997 ◽  
Vol 11 (13) ◽  
pp. 2004-2015 ◽  
Author(s):  
I. Erenburg ◽  
B. Schachter ◽  
R. Mira y Lopez ◽  
L. Ossowski
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Vector Control ◽  
Cancer Cells ◽  
Dominant Negative ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Normal Breast Epithelium ◽  
Anchorage Independent Growth

Abstract Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ERα) isoform, missing exon 3 (ERαΔ3), to the full-length ERα, in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduction of this ratio in cancer cells (P < 0.0001). To test what functions may have been affected by the loss of ERαΔ3, stable clones of MCF-7 cells expressing ectopic ERαΔ3 protein, at the range of physiological ERα, were generated. In vector-transfected controls the ERαΔ3-mRNA and protein were less than 10% while in the ERαΔ3-expressing clones, ERαΔ3-mRNA and protein ranged from 36–76% of the total ERα. Estrogen (E2) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ERαΔ3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ERαΔ3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ERαΔ3-expressing clones was reduced by 50–68%, while their exponential growth rate was only slightly (14.5 ± 5%) lower. The in vivo invasiveness of the ERαΔ3-expressing cells was significantly reduced (P = 0.007) by up to 79%. E2 stimulated anchorage-independent growth of the pMV7 vector control cells, but reduced it to below baseline levels in ERαΔ3 clones. The reduction of the pS2 response to E2 in the ERαΔ3-expressing clones and the E2 block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ERαΔ3. These observations suggest that E2 may activate an additional ERαΔ3-dependent inhibitory pathway. The drastic reduction of ERαΔ3 to ERα ratio in breast cancer, and the fact that when present in breast cancer cells this isoform leads to a suppression, rather than enhancement, of the transformed phenotype by E2 suggests that the regulation of ERα-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

scholarly journals MDM2 Promotes Cell Motility and Invasiveness by Regulating E-Cadherin Degradation

2006 ◽  
Vol 26 (19) ◽  
pp. 7269-7282 ◽  
Author(s):  
Jer-Yen Yang ◽  
Cong S. Zong ◽  
Weiya Xia ◽  
Yongkun Wei ◽  
Mohamed Ali-Seyed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Antibody Array ◽  
Breast Cancer Patients ◽  
Mdm2 Gene ◽  
E Cadherin

ABSTRACT Gene amplification and protein overexpression of MDM2, which is often found in certain types of cancers, indicate that MDM2 plays an important role in tumorigenesis. Interestingly, several clinical reports have demonstrated that amplification of the MDM2 gene correlates with the metastatic stage. Using an antibody array assay, we identified E-cadherin as an MDM2-binding protein and confirmed that E-cadherin is a substrate for the MDM2 E3 ubiquitin ligase. We demonstrate that MDM2 interacts in vivo with E-cadherin, resulting in its ubiquitination and degradation. This regulation appears to be clinically relevant, as we found a significant correlation between high MDM2 and low E-cadherin protein levels in resected tumor specimens recovered from breast cancer patients with lymph node metastases. Ectopic expression of MDM2 in breast cancer cells was found to disrupt cell-cell contacts and enhance cell motility and invasive potential. We found that E-cadherin and MDM2 colocalized on the plasma membrane and in the early endosome, where ubiquitin moieties were attached to E-cadherin. Blocking endocytosis with dominant-negative mutants of dynamin abolished the association of MDM2 with E-cadherin, prevented E-cadherin degradation, and attenuated cell motility as observed by fluorescence microscopy. Thus, we provide evidence to support a novel role for MDM2 in regulating cell adhesions by a mechanism that involves degrading and down-regulating the expression of E-cadherin via an endosome pathway. This novel MDM2-regulated pathway is likely to play a biologically relevant role in cancer metastasis.

scholarly journals Human Breast Cancer Growth Inhibitedin Vivoby a Dominant Negative Pleiotrophin Mutant

1997 ◽  
Vol 272 (27) ◽  
pp. 16733-16736 ◽  
Author(s):  
Nan Zhang ◽  
Rong Zhong ◽  
Zhao-Yi Wang ◽  
Thomas F. Deuel
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Dominant Negative ◽  
Cancer Growth ◽  
Human Breast ◽  
Breast Cancer Growth

scholarly journals Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model

Gene Therapy ◽  
2014 ◽  
Vol 21 (10) ◽  
pp. 903-912 ◽  
Author(s):  
A Okal ◽  
K J Matissek ◽  
S J Matissek ◽  
R Price ◽  
M E Salama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Tumor Regression ◽  
Xenograft Model ◽  
Dominant Negative ◽  
Breast Cancer Xenograft

scholarly journals Evaluation of ACMG Rules for In silico Evidence Strength Using An Independent Computational Tool Absent of Circularities on ATM and CHEK2 Breast Cancer Cases and Controls

2019 ◽  
Author(s):  
Colin C. Young ◽  
Bing-Jian Feng ◽  
Colin B. Mackenzie ◽  
Elodie Girard ◽  
Donglei Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mutation Screening ◽  
Case Control ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cancer Case ◽  
Sequence Variant ◽  
Supporting Evidence ◽  
Variant Classification ◽  
Computational Tool

AbstractThe American College of Medical Genetics and Genomics (ACMG) guidelines for sequence variant classification include two criteria, PP3 and BP4, for combining computational data with other evidence types contributing to sequence variant classification. PP3 and BP4 assert that computational modeling can provide “Supporting” evidence for or against pathogenicity within the ACMG framework. Here, leveraging a meta-analysis of ATM and CHEK2 breast cancer case-control mutation screening data, we evaluate the strength of evidence determined from the relatively simple computational tool Align-GVGD. Importantly, application of Align-GVGD to these ATM and CHEK2 data is free of logical circularities, hidden multiple testing, and use of other ACMG evidence types. For both genes, rare missense substitutions that are assigned the most severe Align-GVGD grade exceed a “Moderate pathogenic” evidence threshold when analyzed in a Bayesian framework; accordingly, we argue that the ACMG classification rules be updated for well-calibrated computational tools. Additionally, congruent with previous analyses of ATM and CHEK2 case-control mutation screening data, we find that both genes have a considerable burden of pathogenic missense substitutions, and that severe ATM rare missense have increased odds ratios compared to truncating and splice junction variants, indicative of a potential dominant-negative effect for those missense substitutions.

scholarly journals Androgen Receptor Highjacks ErbB-2 Nuclear Function to Induce Triple Negative Breast Cancer Growth

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A804-A804
Author(s):  
Agustina Roldán Deamicis ◽  
Robert H Oakley ◽  
Sergio Andonegui Helguera ◽  
Mariela B Lenze ◽  
Santiago Madera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Nuclear Migration ◽  
Subcellular Fractionation ◽  
Gene Signature ◽  
Dominant Negative ◽  
Cox Regression Analysis

Abstract Triple negative breast cancer (TNBC) has poor prognosis and neither established biomarkers nor therapeutic targets. On the one hand the androgen receptor (AR), a steroid hormone receptor (SR) which is expressed in 10-53% of TNBC and proved to be critical for BC proliferation, has been proposed as a new target in TNBC. On the other hand, we and others have shown that membrane ErbB-2 migrates to the nucleus (nuclear ErbB-2, NErbB-2) where it binds DNA at HER-2 associated sequences (HAS) to regulate BC proliferation and migration. Since we have previously shown a functional interplay between growth factors and SR signaling pathways in BC, we propose the existence of an interaction between AR and ErbB-2 which is involved in NErbB-2+/AR+ BC growth. The experimental model used was the human TNBC cell line MDA-MB-453 which displays high expression levels of AR and NErbB-2. By Western Blot (WB) we found that dihydrotestosterone (DHT) treatment for short times (minutes) did not regulate ErbB-2 phosphorylation status at residues Tyr1221/1222 and 1248 which were constitutively activated. However, DHT led to an increase in ErbB-2 phosphorylation at residue Tyr877 which we have proved to be required for ErbB-2 nuclear migration. The latter effect was blocked by the AR antagonist enzalutamide (enza). Blockage of Src activity with dasatinib inhibited DHT-induced ErbB-2 phosphorylation at Tyr877. By Immunofluorescence and confocal microscopy analyses and subcellular fractionation studies we demonstrated that DHT induced ErbB-2 nuclear migration which was inhibited by enza. By chIP we found that DHT induced ErbB-2 recruitment to a HAS site in ERK5, a gene involved in BC proliferation, and to a HAS site in FKBP5, a classical AR responsive gene. By WB we demonstrated that transfection with an ErbB-2 mutant which is unable to translocate to the nucleus and functions as a dominant negative inhibitor of ErbB-2 nuclear migration (hErbB-2ΔNLS), inhibited FKBP51 up-regulation by DHT. Finally, by microarray and bioinformatics analysis we identified 315 differentially expressed genes (DEGs) in the presence of DHT and NErbB-2 eviction. Enrichment analyses showed that the DEGs belonged to the immune response and interferon pathways. Kaplan-Meier analysis revealed that the expression of 6 genes was significantly associated with overall survival in TNBC patients from the METABRIC cohort: CXCL10, TAP1, STAT1, NMI, HLA-A and NLRC5. Multivariate Cox regression analysis identified the combined expression of the 6 genes as an independent predictor of better clinical outcome in TNBC (HR: 0.56, 95% CI 0.38-0.82, P = 0.003). In conclusion, our findings evidence that DHT-activated AR induces Src-mediated ErbB-2 rapid activation and its migration to the nucleus where it binds to HAS sites in the DNA. Moreover, based on the DEGs of NErbB-2 eviction in presence of DHT we identified a gene signature associated with favorable outcome in TNBC.

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