Title: Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε.
Authors: Sviderskiy, Vladislav O; Blumenberg, Lili; Gorodetsky, Elizabeth; Karakousi, Triantafyllia R; Hirsh, Nicole; Alvarez, Samantha W; Terzi, Erdem M; Kaparos, Efiyenia; Whiten, Gabrielle C; Ssebyala, Shakirah; Tonzi, Peter; Mir, Hannan; Neel, Benjamin G; Huang, Tony T; Adams, Sylvia; Ruggles, Kelly V; Possemato, Richard
Published In Mol Cell, (2020 11 19)
Abstract: Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.
PubMed ID: 33152268
MeSH Terms: Animals; Apoptosis; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology*; Carcinoma, Basal Cell/genetics; Carcinoma, Basal Cell/metabolism; Carcinoma, Basal Cell/pathology*; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase 2/genetics; Cyclin-Dependent Kinase 2/metabolism*; DNA Damage; DNA Polymerase II/genetics; DNA Polymerase II/metabolism*; Female; Genomic Instability*; Humans; Mice; Mice, Inbred NOD; Phosphorylation; Poly-ADP-Ribose Binding Proteins/genetics; Poly-ADP-Ribose Binding Proteins/metabolism*; Signal Transduction; Tumor Cells, Cultured