Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers.
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.
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Jin-Ah
JA
Kim
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Ying
Y
Tan
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Xian
X
Wang
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Xixi
X
Cao
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Jamunarani
J
Veeraraghavan
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Yulong
Y
Liang
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Pathology &Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Dean P
DP
Edwards
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Shixia
S
Huang
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Xuewen
X
Pan
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Kaiyi
K
Li
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Rachel
R
Schiff
Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Xiao-Song
XS
Wang
D000465:Algorithms; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D015894:Genome, Human; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D011494:Protein Kinases; C121377:protein kinase U; D017346:Protein Serine-Threonine Kinases; C000627208:Tlk2 protein, mouse
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