ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a γ-secretase inhibitor

Osipo, Clodia; Patel, Parul; Rizzo, Paola; Clementz, Anthony G.; Hao, Lu; Golde, Todd E.; Miele, Lucio

doi:10.1038/onc.2008.149

Cited by 194 publications

(184 citation statements)

References 68 publications

(75 reference statements)

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“…Targeting the GS complex may find a role in re-sensitizing cancer cells to chemotherapy, hormonal and targeted therapies, given the upregulation of notch 1 upon treatment with oxaliplatin in colon cancer [28], and tamoxifen and trastuzumab in BC cell lines [28,34,35]. The lack of tissue specificity of GSIs, however, results in significant gastrointestinal toxicity and lethargy [36], limiting their clinical appeal.…”

Section: Discussionmentioning

confidence: 99%

Biological and clinical implications of nicastrin expression in invasive breast cancer

Filipović

Gronau

Green

et al. 2010

Breast Cancer Res Treat

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Nicastrin is an essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has prognostic value or potential as a therapeutic target in breast cancer.The suitability of nicastrin as a target in breast cancer (BC) was assessed using BC tissue microarrays (TMAs) (n = 1050), and its biological role in vitro was evaluated in BC cell lines following gene silencing. Nicastrin blocking antibodies were developed and evaluated for their suitability as potential clinical therapeutics.TMA and cell line analysis confirmed that nicastrin expression was upregulated in BC compared to normal breast cells.In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with ERα expression, patient age and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ERα -ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch 1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120catenin at cell-cell junctions in MCF7 cells. Nicastrin silencing in invasive MDA-MB-231 cells resulted in loss of vimentin expression and a marked reduction in both cell motility and invasion; which was concomitant with the de novo formation of cell-cell junctions characterised by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial-to-mesenchymal transistion during BC progression.Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of BC cells in vitro. This supports our hypothesis that a nicastrin blocking antibody could be used to limit metastatic dissemination in invasive BC.3

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Section: Discussionmentioning

confidence: 99%

Biological and clinical implications of nicastrin expression in invasive breast cancer

Filipović

Gronau

Green

et al. 2010

Breast Cancer Res Treat

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“…[19][20][21][22][23][24][25] Moreover, the overall response rate of women diagnosed with HER2-positive metastatic breast cancer and treated with trastuzumab as a single first-line agent is only 26%; that is, > 70% of HER2-overexpressing metastatic breast carcinomas show a resistance to trastuzumab ab initio. A variety of possible mechanisms of escape from trastuzumab appear to involve many of the same biomarkers that have been implicated in the biology of CS-like cells: e.g., the overexpression of the stem cell-related marker CD44, leading to a loss or blockage of the trastuzumab-binding site at the extracellular domain of HER2; 26,27 the upregulation of stem cell markers, such as CXCR4, β1 integrin or Notch-1, [28][29][30][31][32] leading to the activation of alternative pathways circumventing HER2 signaling and the upregulation of pro-survival mediators, such as the inhibitor of apoptosis survivin. 33 Accordingly, it has been suggested that, although trastuzumab effectively targets cancer-initiating cells, a clinical resistance to trastuzumab may counter-intuitively be driven by breast CSCs.…”

Section: Epithelial-to-mesenchymal Transition (Emt) Confers Primary Rmentioning

confidence: 99%

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

et al. 2012

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“…Osipo et al have recently reported that Her2/neu overexpression inhibits Notch signaling, possibly by altering ligand availability at the cell membrane [40]. Treatment of Her2/Neu overexpressing breast cancer cells with trastuzumab or with a dual EGF receptor-Her2/neu tyrosine kinase inhibitor caused re-activation of Notch signaling, and increased dependence on Notch for proliferation and survival.…”

Section: Rationally Designed Combination Regimensmentioning

confidence: 99%

Rational targeting of Notch signaling in breast cancer

Miele¹

2008

Expert Review of Anticancer Therapy

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ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a γ-secretase inhibitor

Cited by 194 publications

References 68 publications

Biological and clinical implications of nicastrin expression in invasive breast cancer

Biological and clinical implications of nicastrin expression in invasive breast cancer

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

Rational targeting of Notch signaling in breast cancer

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