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

  • Nat Commun. 2016 Oct 3:7:12991. doi: 10.1038/ncomms12991.
Jin-Ah Kim  1  2  3 ,  Ying Tan  1  2  3 ,  Xian Wang  1  2  3  4  5 ,  Xixi Cao  1  2  3 ,  Jamunarani Veeraraghavan  1  2  3 ,  Yulong Liang  6 ,  Dean P Edwards  2  7  8 ,  Shixia Huang  2  8 ,  Xuewen Pan  9 ,  Kaiyi Li  6 ,  Rachel Schiff  1  2  3  8 ,  Xiao-Song Wang  1  2  3  4  5  8
Affiliations
  • 1. Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 3. Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 4. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
  • 5. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
  • 6. Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 7. Department of Pathology &Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 8. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 9. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
PMID: 27694828 DOI: 10.1038/ncomms12991
Abstract

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.