@article { , title = {Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells}, abstract = {The goal of targeted cancer therapies is to specifically block oncogenic signalling, thus maximising efficacy, while reducing side-effects to patients. The gamma-secretase (GS) complex is an attractive therapeutic target in haematological malignancies and solid tumours with major pharmaceutical activity to identify optimal inhibitors. Within GS, nicastrin (NCSTN) offers an opportunity for therapeutic intervention using blocking monoclonal antibodies (mAbs). Here we explore the role of anti-nicastrin monoclonal antibodies, which we have developed as specific, multi-faceted inhibitors of proliferation and invasive traits of triple-negative breast cancer cells. We use 3D in vitro proliferation and invasion assays as well as an orthotopic and tail vail injection triple-negative breast cancer in vivo xenograft model systems. RNAScope assessed nicastrin in patient samples. Anti-NCSTN mAb clone-2H6 demonstrated a superior anti-tumour efficacy than clone-10C11 and the RO4929097 small molecule GS inhibitor, acting by inhibiting GS enzymatic activity and Notch signalling in vitro and in vivo. Confirming clinical relevance of nicastrin as a target, we report evidence of increased NCSTN mRNA levels by RNA in situ hybridization (RNAScope) in a large cohort of oestrogen receptor negative breast cancers, conferring independent prognostic significance for disease-free survival, in multivariate analysis. We demonstrate here that targeting NCSTN using specific mAbs may represent a novel mode of treatment for invasive triple-negative breast cancer, for which there are few targeted therapeutic options. Furthermore, we propose that measuring NCSTN in patient samples using RNAScope technology may serve as companion diagnostic for anti-NCSTN therapy in the clinic.}, doi = {10.1007/s10549-014-3119-z}, eissn = {1573-7217}, issn = {0167-6806}, issue = {2}, journal = {Breast Cancer Research and Treatment}, pages = {455-462}, publicationstatus = {Published}, publisher = {Springer Verlag}, url = {https://nottingham-repository.worktribe.com/output/1172178}, volume = {148}, keyword = {Nottingham Breast Cancer Research Centre, Nicastrin, Breast cancer, Monoclonal antibodies}, year = {2014}, author = {Filipovi?, Aleksandra and Lombardo, Ylenia and Fronato, Monica and Abrahams, Joel and Aboagye, Eric and Nguyen, Quang-De and d’Aqua, Barbara Borda and Ridley, Anne and Green, Andrew and Rahka, Emad and Ellis, Ian and Recchi, Chiara and Przulj, Natasa and Sarajli?, Anida and Alattia, Jean-Rene and Fraering, Patrick and Deonarain, Mahendra and Coombes, R. Charles} }