Clinical & Experimental Metastasis

, Volume 30, Issue 4, pp 483–495 | Cite as

LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice

  • Rong Li
  • Judy Doherty
  • Juliana Antonipillai
  • Sheng Chen
  • Mark Devlin
  • Kathryn Visser
  • Jonathan Baell
  • Ian Street
  • Robin L. AndersonEmail author
  • Ora BernardEmail author
Research Paper


Metastasis is the major cause of morbidity and mortality in cancer patients. An understanding of the genes that regulate metastasis and development of therapies to target these genes is needed urgently. Since members of the LIM kinase (LIMK) family are key regulators of the actin cytoskeleton and are involved in cell motility and invasion, LIMK is considered to be a good therapeutic target for metastatic disease. Here we investigated the consequences of LIMK inhibition on growth and metastasis of human and mouse mammary tumors. LIMK activity was reduced in tumor cells by expression of dominant-negative LIMK1, by RNA interference or with a selective LIMK inhibitor. The extent of phosphorylation of the LIMK substrate, cofilin, of proliferation and invasion in 2D and 3D culture and of tumor growth and metastasis in mice were assessed. Inhibition of LIMK activity efficiently reduced the pro-invasive properties of tumor cells in vitro. Tumors expressing dominant-negative LIMK1 grew more slowly and were less metastatic in mice. However, systemic administration of a LIMK inhibitor did not reduce either primary tumor growth or spontaneous metastasis. Surprisingly, metastasis to the liver was increased after administration of the inhibitor. These data raise a concern about the use of systemic LIMK inhibitors for the treatment of metastatic breast cancer.


LIM kinase inhibitors Breast cancer Metastasis Actin cytoskeleton Therapy 



LIM kinase


Actin depolymerizing factor


Filamentous action




Small interfering RNA



We thank Christina Restall for technical assistance and advice, Dr Bala Murthy for advice on FACS analysis, Dr. Roger Tsien for provision of the cherry fluorescent protein vector, Alison Gregg and Julia Morizzi for analysis of BMS3 levels in mice, Dr. Siddhartha Deb for pathology advice and Dr. Duncan Campbell for assistance with the statistical analysis. This work was supported by grants from the NIH (R21CA098229) and from the NHMRC of Australia, Fellowship support from NHMRC (OB) and from NBCF (Australia) (RLA). The authors acknowledge financial support from the Cancer Therapeutics CRC, established and supported under the Australian Government’s Cooperative Research Centre Program.

Conflict of interest

No potential conflicts of interest were disclosed.

Supplementary material

10585_2012_9553_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1158 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Rong Li
    • 1
  • Judy Doherty
    • 2
    • 5
  • Juliana Antonipillai
    • 1
  • Sheng Chen
    • 1
  • Mark Devlin
    • 2
    • 5
  • Kathryn Visser
    • 2
    • 5
  • Jonathan Baell
    • 3
    • 5
  • Ian Street
    • 3
    • 5
    • 6
  • Robin L. Anderson
    • 2
    • 4
    Email author
  • Ora Bernard
    • 1
    • 7
    Email author
  1. 1.St Vincent’s Institute of Medical ResearchMelbourneAustralia
  2. 2.Peter MacCallum Cancer CentreMelbourneAustralia
  3. 3.The Walter and Eliza Hall Institute of Medical ResearchMelbourneAustralia
  4. 4.The Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneAustralia
  5. 5.Cancer Therapeutics Cooperative Research CentreBundooraAustralia
  6. 6.Department of Medical BiologyThe University of MelbourneMelbourneAustralia
  7. 7.Department of MedicineThe University of Melbourne, St Vincent’s HospitalMelbourneAustralia

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