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Biological and clinical implications of nicastrin expression in invasive breast cancer

Filipović, Aleksandra; Gronau, Julian Hendrik; Green, Andrew R.; Wang, Jayson; Vallath, Sabari; Shao, Dongmin; Rasul, Sabeena; Ellis, Ian O.; Yagüe, Ernesto; Sturge, Justin; Coombes, R. Charles

Authors

Aleksandra Filipović

Julian Hendrik Gronau

Andrew R. Green

Jayson Wang

Sabari Vallath

Dongmin Shao

Sabeena Rasul

Ian O. Ellis

Ernesto Yagüe

R. Charles Coombes



Abstract

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 (BC). The suitability of nicastrin as a target in 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 ERa expression, patient age, and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ERa -ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120 catenin 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 characterized by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial to mesenchymal transition 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.

Citation

Filipović, A., Gronau, J. H., Green, A. R., Wang, J., Vallath, S., Shao, D., …Coombes, R. C. (2010). Biological and clinical implications of nicastrin expression in invasive breast cancer. Breast cancer research and treatment, 125(1), 43-53. doi:10.1007/s10549-010-0823-1

Journal Article Type Article
Acceptance Date Feb 24, 2010
Online Publication Date Mar 12, 2010
Publication Date 2011-01
Journal BREAST CANCER RESEARCH AND TREATMENT
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 125
Issue 1
Pages 43-53
DOI https://doi.org/10.1007/s10549-010-0823-1
Keywords Breast cancer; Nicastrin; Gamma secretase; Invasion; Monoclonal antibody
Public URL https://hull-repository.worktribe.com/output/417739
Publisher URL http://www.springerlink.com/content/h4243855l5g26224/