Matches in SemOpenAlex for { <https://semopenalex.org/work/W2488003465> ?p ?o ?g. }
Showing items 1 to 74 of
74
with 100 items per page.
- W2488003465 abstract "While the Notch pathway is reportedly activated in breast cancer, the molecular mechanisms leading to its aberrant activation remain elusive, hampering the optimal development of Notch inhibitors in the clinics. In an effort to identify predictive biomarkers of response to Notch targeted therapies in breast cancer, we used several computational approaches, including novel algorithms for detecting complex structural rearrangements, to analyze next generation sequencing and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. We identified simple mutations and complex rearrangements in NOTCH1, NOTCH2 and NOTCH3 that compromised the function of the PEST domain, a negative regulatory domain controlling the duration of active Notch signaling. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain alterations, at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple negative breast cancer (TNBC) subtype. We also sequenced a panel of breast cancer xenograft models and identified models that harbor functionally equivalent PEST domain alterations. These models were significantly more sensitive to a gamma secretase inhibitor (GSI) compared to models without Notch alterations. Gene expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by GSI. In summary, we demonstrated that Notch pathway is activated via multiple mutational mechanisms primarily involving the PEST domains of NOTCH1, NOTCH2 and NOTCH3. Collectively, approximately 13% of TNBC exhibits a genetic alteration coupled with pathway up-regulation and these alterations may serve as biomarkers to identify patients most likely to respond to Notch inhibitors. Citation Format: Kai Wang, Qin Zhang, Danan Li, Keith Ching, Cathy Zhang, Xianxian Zheng, Mark Ozeck, Stephanie Shi, Xiaorong Li, Hui Wang, Paul Rejto, James Christensen, Peter Olson. Identification of drug-sensitive Notch receptor alterations in human breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-52." @default.
- W2488003465 created "2016-08-23" @default.
- W2488003465 creator A5016938641 @default.
- W2488003465 creator A5020129424 @default.
- W2488003465 creator A5022683638 @default.
- W2488003465 creator A5042557251 @default.
- W2488003465 creator A5045702100 @default.
- W2488003465 creator A5056640120 @default.
- W2488003465 creator A5063127492 @default.
- W2488003465 creator A5073531557 @default.
- W2488003465 creator A5074923974 @default.
- W2488003465 creator A5081727526 @default.
- W2488003465 creator A5090085904 @default.
- W2488003465 creator A5090366405 @default.
- W2488003465 creator A5091310917 @default.
- W2488003465 date "2015-11-15" @default.
- W2488003465 modified "2023-09-25" @default.
- W2488003465 title "Abstract A1-52: Identification of drug-sensitive Notch receptor alterations in human breast cancer" @default.
- W2488003465 doi "https://doi.org/10.1158/1538-7445.transcagen-a1-52" @default.
- W2488003465 hasPublicationYear "2015" @default.
- W2488003465 type Work @default.
- W2488003465 sameAs 2488003465 @default.
- W2488003465 citedByCount "0" @default.
- W2488003465 crossrefType "proceedings-article" @default.
- W2488003465 hasAuthorship W2488003465A5016938641 @default.
- W2488003465 hasAuthorship W2488003465A5020129424 @default.
- W2488003465 hasAuthorship W2488003465A5022683638 @default.
- W2488003465 hasAuthorship W2488003465A5042557251 @default.
- W2488003465 hasAuthorship W2488003465A5045702100 @default.
- W2488003465 hasAuthorship W2488003465A5056640120 @default.
- W2488003465 hasAuthorship W2488003465A5063127492 @default.
- W2488003465 hasAuthorship W2488003465A5073531557 @default.
- W2488003465 hasAuthorship W2488003465A5074923974 @default.
- W2488003465 hasAuthorship W2488003465A5081727526 @default.
- W2488003465 hasAuthorship W2488003465A5090085904 @default.
- W2488003465 hasAuthorship W2488003465A5090366405 @default.
- W2488003465 hasAuthorship W2488003465A5091310917 @default.
- W2488003465 hasConcept C104317684 @default.
- W2488003465 hasConcept C121608353 @default.
- W2488003465 hasConcept C161879069 @default.
- W2488003465 hasConcept C2780110267 @default.
- W2488003465 hasConcept C501734568 @default.
- W2488003465 hasConcept C502942594 @default.
- W2488003465 hasConcept C530470458 @default.
- W2488003465 hasConcept C54355233 @default.
- W2488003465 hasConcept C70721500 @default.
- W2488003465 hasConcept C86803240 @default.
- W2488003465 hasConceptScore W2488003465C104317684 @default.
- W2488003465 hasConceptScore W2488003465C121608353 @default.
- W2488003465 hasConceptScore W2488003465C161879069 @default.
- W2488003465 hasConceptScore W2488003465C2780110267 @default.
- W2488003465 hasConceptScore W2488003465C501734568 @default.
- W2488003465 hasConceptScore W2488003465C502942594 @default.
- W2488003465 hasConceptScore W2488003465C530470458 @default.
- W2488003465 hasConceptScore W2488003465C54355233 @default.
- W2488003465 hasConceptScore W2488003465C70721500 @default.
- W2488003465 hasConceptScore W2488003465C86803240 @default.
- W2488003465 hasLocation W24880034651 @default.
- W2488003465 hasOpenAccess W2488003465 @default.
- W2488003465 hasPrimaryLocation W24880034651 @default.
- W2488003465 hasRelatedWork W13070214 @default.
- W2488003465 hasRelatedWork W13408133 @default.
- W2488003465 hasRelatedWork W24200575 @default.
- W2488003465 hasRelatedWork W25226527 @default.
- W2488003465 hasRelatedWork W28795566 @default.
- W2488003465 hasRelatedWork W30571848 @default.
- W2488003465 hasRelatedWork W35917995 @default.
- W2488003465 hasRelatedWork W36085773 @default.
- W2488003465 hasRelatedWork W8041353 @default.
- W2488003465 hasRelatedWork W8371980 @default.
- W2488003465 isParatext "false" @default.
- W2488003465 isRetracted "false" @default.
- W2488003465 magId "2488003465" @default.
- W2488003465 workType "article" @default.