Journal
MOLECULAR CANCER RESEARCH
Volume 14, Issue 10, Pages 920-927Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0161
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Funding
- Susan G. Komen foundation [PDF12231561]
- CDMRP grants [W81XWH-12-1-0166, W81XWH-12-1-0167, W81XWH-13-1-0431]
- NIH [CA181368, CA183976, P30-125123-06, P30 AI036211, P30 CA125123, S10 RR024574]
- Bayer College of Medicine Dan L. Duncan Cancer Center Biostatistics and Informatics Shared Resource [NCIP30 CA125123]
- Cytometry and Cell Sorting Core at the Bayer College of Medicine
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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 G(2)-Mcheckpoint 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. Implications: Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness. (C) 2016 AACR.
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