Triple negative breast cancers (TNBCs) comprise only a subset of all breast cancers, yet they are highly aggressive and offer the worst prognosis. A characteristic feature of TNBCs is their strikingly complex genomic profiles, highlighted by genomic rearrangements and chromosome structural aberrations. However, mechanisms responsible for the chromosomal alterations that potentially drive tumorigenesis remain unclear. We postulate that TNBCs depend upon the alternative, Lig4-independent NHEJ (A-NHEJ) pathway for DNA repair. We will use mouse models and human tumor samples to understand how progressive telomere dysfunction and activation of the A-NHEJ pathway generate pro-oncogenic chromosomal aberrations and the stepwise accumulation of mutational changes in favor of breast tumor initiation and progression.
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