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

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  • Jin-Ah Kim

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Ying Tan

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Xian Wang

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    University of Pittsburgh Cancer Institute, University of Pittsburgh)

  • Xixi Cao

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Jamunarani Veeraraghavan

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Yulong Liang

    (Baylor College of Medicine)

  • Dean P. Edwards

    (Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Shixia Huang

    (Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Xuewen Pan

    (Baylor College of Medicine)

  • Kaiyi Li

    (Baylor College of Medicine)

  • Rachel Schiff

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Xiao-Song Wang

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    University of Pittsburgh Cancer Institute, University of Pittsburgh)

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.

Suggested Citation

  • Jin-Ah Kim & Ying Tan & Xian Wang & Xixi Cao & Jamunarani Veeraraghavan & Yulong Liang & Dean P. Edwards & Shixia Huang & Xuewen Pan & Kaiyi Li & Rachel Schiff & Xiao-Song Wang, 2016. "Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers," Nature Communications, Nature, vol. 7(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12991
    DOI: 10.1038/ncomms12991
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    Cited by:

    1. Bertrand Simon & Hua Jane Lou & Clotilde Huet-Calderwood & Guangda Shi & Titus J. Boggon & Benjamin E. Turk & David A. Calderwood, 2022. "Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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