title: Amplification of TLK2 Induces Genomic Instability via Impairing the G2-M Checkpoint.
abstract: Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle-associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor-positive (ER+) breast cancers. In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2-M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instability in aggressive ER+breast cancers.
  
  
  
  Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness. Mol Cancer Res; 14(10); 920-7. ©2016 AACR.
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Anurag
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Jamunarani
authors.initials: J
authors.lastname: Veeraraghavan
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Kaiyi
authors.initials: K
authors.lastname: Li
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Women's Cancer Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. wangx13@pitt.edu.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D011494:Protein Kinases / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D011494:Protein Kinases; C121377:protein kinase U