RNF168 deficiency exacerbates R-loops and causes synthetic lethality in BRCA1/2-deficient tumors
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF (Thermo Scientific Instrument Model)
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Brian Raught
PROVIDER: MSV000084981 | MassIVE | Wed Feb 19 15:24:00 GMT 2020
SECONDARY ACCESSION(S): PXD017625
REPOSITORIES: MassIVE
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Project description:BackgroundBasal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed.MethodsMost BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers.ResultsHeterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfr? signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfr? in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfr? and its downstream target Pkc? suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells.ConclusionsOur work offers the first genetic and biochemical evidence that PDGFR?-PKC? signaling is repressed by BRCA1, which establishes PDGFR?-PKC? signaling as a therapeutic target for BRCA1-deficient breast cancers.
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