figure posted on 2023-04-03, 17:01 authored by Jin-Ah Kim, Meenakshi Anurag, Jamunarani Veeraraghavan, Rachel Schiff, Kaiyi Li, Xiao-Song Wang
Figure S1. Correlation of the genomic instability index and copy number breakpoint index with AURKA or PLK1 expression (RNAseq) in 1083 invasive breast cancers based on Spearman's correlation statistics. Figure S2. Association of TLK2, AURKA and PLK1 overexpression with chromosome instability (CIN) in breast cancer. Figure S3. Representative microscope images of γ-H2AX foci formation assay showing delayed DSB repair in T47D or MCF10A cells inducibly overexpressing TLK2. Figure S4. In response to irradiation (IR), TLK2 forms foci that partially co-localize with γ-H2AX foci. Figure S5. TLK2 overexpression led to reduced accumulation of G2/M phase cells in response to IR. Figure S6. The mechanisms of G2/M checkpoint signaling in response to irradiation.
Susan G. Komen foundation
Bayer College of Medicine
Dan L. Duncan Cancer Center Biostatistics
Informatics Shared Resource
ARTICLE ABSTRACTManaging 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.Implications: 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.