HER2/neu antisense targeting of human breast carcinoma

Roh, Haeri; Pippin, James A.; Green, Douglas W.; Boswell, Craig; Hirose, Christopher T; Mokadam, Nahush A.; Drebin, Jeffrey A.

doi:10.1038/sj.onc.1204001

Cited by 46 publications

(39 citation statements)

References 32 publications

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“…Overexpression of similar ␤-catenin mutants leads to neoplastic transformation of E1A-immortalized epithelial cells and stimulated proliferation of p53-or ARF-null mouse embryo fibroblasts (36,37). Consistent with these results, specific reduction of ␤-catenin in APC-mutant colon cancer cells by antisense oligonucleotides or small interference RNA inhibited the proliferation, anchorage-independent growth, and cellular invasiveness in vitro and neoplastic growth of xenografts in animals (27,28,38). In keeping with the role of ␤-catenin in cell growth, activation of the RXRmediated pathway reduced cell proliferation (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…4c), indicating that ␤-catenin RXR Agonists Inhibit Growth of ⌬N␤-Catenin-expressing Cells via RXR-Dysregulation of ␤-catenin by mutations in the N-terminal GSK3␤-targeted sites is associated with cancer cell growth. Specific reduction of ␤-catenin protein levels by antisense oligonucleotides or small interference RNA in APC mutant colon cancer cells inhibited cell proliferation, anchorageindependent growth, and cellular invasiveness in vitro (27,28). We have investigated whether the RXR␣-mediated degradation of ⌬N␤-catenin affected the cell proliferation rate.…”

Section: Figmentioning

confidence: 99%

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Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Xiao

Ghosn

Hinchman

et al. 2003

Journal of Biological Chemistry

139

147

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␤-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free ␤-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3␤ (GSK3␤) or p53-inducible Siah-1. Dysregulation of ␤-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of ␤-catenin. In this proteasomal pathway, RXR agonists induce degradation of ␤-catenin and RXR␣ and repress ␤-catenin-mediated transcription. In vivo, ␤-catenin interacts with RXR␣ in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3␤ inhibitors or deletion of the GSK3␤-targeted sequence from ␤-catenin. In APC-and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous ␤-catenin via RXR␣. Interestingly, deletion of the RXR␣ A/B region abolished ligand-induced ␤-catenin degradation but not RXR␣-mediated transactivation. RXR␣-mediated inactivation of oncogenic ␤-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of ␤-catenin turnover and related biological events.

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Section: Discussionsupporting

confidence: 71%

Section: Figmentioning

confidence: 99%

Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Xiao

Ghosn

Hinchman

et al. 2003

Journal of Biological Chemistry

139

147

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“…Our findings give the first proof for an active involvement of EpCAM in proliferation control and cell signalling in vitro as has already been shown for other tumor antigens such as EGF-R ( Davies and Chamberlin, 1996) and Her2/neu (Meden and Kuhn, 1997;Roh et al, 2000). The strong detrimental effects of the inhibition of EpCAM in carcinoma cells observed in vitro are hitherto encouraging and reminiscent of the inhibition of the expression of the oncogene Her2/neu (Roh et al, 2000).…”

Section: Discussionmentioning

confidence: 58%

“…The strong detrimental effects of the inhibition of EpCAM in carcinoma cells observed in vitro are hitherto encouraging and reminiscent of the inhibition of the expression of the oncogene Her2/neu (Roh et al, 2000). Therefore, the specific inhibition of EpCAM in tumours may represent a new therapeutic approach to repress carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

Münz¹,

et al. 2004

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Epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein expressed on adenomatous and simple epithelia, where it is involved in homophilic adhesion at the basolateral membrane. Carcinomas strongly overexpress EpCAM through an, as yet, unknown mechanism. Interestingly, otherwise EpCAM-negative squamous epithelia are seen to express EpCAM concomitant with their transformation and de-differentiation. The amount of EpCAM and the number of expressing cells both increase with the grade of dysplasia. Despite an important amount of data correlating the expression of EpCAM with cellular proliferation and de-differentiation, such as the coexpression with Ki-67, a marker for proliferation, it is unknown whether EpCAM may directly contribute to carcinogenesis. Here, we show that EpCAM has a direct impact on cell cycle and proliferation, and the ability to rapidly upregulate the proto-oncogene c-myc and cyclin A/E. Human epithelial 293 cells as well as murine NIH3T3 fibroblasts expressing EpCAM had a decreased requirement for growth factors, enhanced metabolic activity and colony formation capacity. Importantly, the inhibition of EpCAM expression with antisense mRNA led to a strong decrease in proliferation and metabolism in human carcinoma cells. Moreover, domain swapping experiments demonstrated that the intracellular part of EpCAM is necessary and sufficient to transduce the effects described. Thus, the data presented here highlight the role of EpCAM, demonstrating for the first time a direct link to cell cycle and proliferation.

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“…A reduction in the constitutive activity of this pathway in colon cancer, for example by reducing levels of signalling b-catenin, reverses this earliest and most essential oncogenic signal and has been shown to be an effective antitumour strategy in vitro and in vivo Roh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

et al. 2006

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Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/b-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of b-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of b-catenin were assessed by immunoblotting, and also the localization of b-catenin was shown by green fluorescent protein-tagged b-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/b-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/b-catenin pathway activity in these cells.

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HER2/neu antisense targeting of human breast carcinoma

Cited by 46 publications

References 32 publications

Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

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