Subject(s)
Arrhythmias, Cardiac/therapy , Defibrillators, Implantable , Heart Neoplasms/therapy , Melanoma/secondary , Molecular Targeted Therapy/methods , Skin Neoplasms , Adult , Antineoplastic Agents/administration & dosage , Heart Neoplasms/secondary , Humans , Imidazoles/administration & dosage , Male , Melanoma/therapy , Oximes/administration & dosage , Positron Emission Tomography Computed Tomography , Protein Kinase Inhibitors/therapeutic use , Pyridones/administration & dosage , Pyrimidinones/administration & dosageABSTRACT
Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , Receptor, Notch1/genetics , Signal Transduction/genetics , Transcriptional Activation , Apoptosis/drug effects , Apoptosis/genetics , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Coculture Techniques , Flow Cytometry , Humans , Microscopy, Fluorescence , RNA Interference , Receptor, Notch1/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SUMO-1 Protein/genetics , SUMO-1 Protein/metabolism , Salicylates/pharmacology , Signal Transduction/drug effects , Small Ubiquitin-Related Modifier Proteins/genetics , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation/drug effects , Sumoylation/genetics , Ubiquitin-Activating Enzymes/genetics , Ubiquitin-Activating Enzymes/metabolism , Ubiquitin-Conjugating Enzymes/genetics , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitins/genetics , Ubiquitins/metabolismABSTRACT
Serum galactomannan (GM) antigen detection is not recommended for defining invasive aspergillosis (IA) in children undergoing aggressive chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT). The ability of the GM test to identify IA in children was retrospectively evaluated in a cohort of children. Test performance was evaluated on samples that were collected during 195 periods at risk of IA. Proven IA was diagnosed in seven periods, all with positive GM test results (true positives, 4%), and possible IA was diagnosed in 15 periods, all with negative GM test results (false negatives, 8%). The test result was positive with negative microbiological, histological and clinical features in three periods (false positives, 1%), and in 170 periods it was negative with negative microbiological, histological and clinical features (true negatives, 87%). The sensitivity was 0.32 and the specificity was 0.98; the positive predictive value was 0.70 and the negative predictive value was 0.92. The efficiency of the test was 0.91, the positive likelihood ratio was 18.3, and the negative likelihood ratio was 1.4. The probability of missing an IA because of a negative test result was 0.03. Test performance proved to be better during at-risk periods following chemotherapy than in periods following allogeneic HSCT. The GM assay is useful for identifying periods of IA in children undergoing aggressive chemotherapy or allogeneic HSCT.
