Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers

• Published in: Nature communications Vol. 7; no. 1; pp. 12991 - 17
• Main Authors: Kim, Jin-Ah, Tan, Ying, Wang, Xian, Cao, Xixi, Veeraraghavan, Jamunarani, Liang, Yulong, Edwards, Dean P., Huang, Shixia, Pan, Xuewen, Li, Kaiyi, Schiff, Rachel, Wang, Xiao-Song
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.10.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/2; 13/31; 13/89; 38; 38/32; 631/67/1347; 631/67/68; 631/67/69; 82; 82/80; 96; Algorithms; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Cycle; Cell Line, Tumor; Datasets; Drug Design; Endocrine therapy; Estrogen Receptor alpha - genetics; Female; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes; Genome, Human; Genomes; Humanities and Social Sciences; Humans; Kinases; MCF-7 Cells; Medical schools; Medicine; Mice; multidisciplinary; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Phenotype; Protein Kinases - genetics; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction; Tumors; Pittsburgh Pennsylvania; United States > US; Texas; Pennsylvania
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12991

More aggressive and therapy-resistant oestrogen receptor (ER)-positive breast cancers remain a great clinical challenge. Here our integrative genomic analysis identifies tousled-like kinase 2 ( TLK2 ) as a candidate kinase target frequently amplified in ∼10.5% of ER-positive breast tumours. The resulting overexpression of TLK2 is more significant in aggressive and advanced tumours, and correlates with worse clinical outcome regardless of endocrine therapy. Ectopic expression of TLK2 leads to enhanced aggressiveness in breast cancer cells, which may involve the EGFR/SRC/FAK signalling. Conversely, TLK2 inhibition selectively inhibits the growth of TLK2 -high breast cancer cells, downregulates ERα, BCL2 and SKP2, impairs G1/S cell cycle progression, induces apoptosis and significantly improves progression-free survival in vivo . We identify two potential TLK2 inhibitors that could serve as backbones for future drug development. Together, amplification of the cell cycle kinase TLK2 presents an attractive genomic target for aggressive ER-positive breast cancers. Luminal B oestrogen receptor positive breast cancers are generally aggressive tumors with poor outcomes. Here, the authors show that the kinase TLK2 is amplified and overexpressed in these tumors and correlates with reduced survival, TLK2 inhibition induces apoptosis in vitro and improves survival in mice.