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

Li, Rong and Doherty, Judy and Antonipillai, Juliana and Chen, Sheng and Devlin, Mark and Visser, Kathryn and Baell, Jonathan and Street, Ian and Anderson, Robin L and Bernard, Ora (2012) LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. Clinical and Experimental Metastasis, 30 (4). pp. 483-495. ISSN 0262-0898 (print) 1573-7276 (online)

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: ResPubID26449, LIM kinase, inhibitors, breast cancer, metastasis, actin cytoskeleton, therapy
Subjects: FOR Classification > 0304 Medicinal and Bimolecular Chemistry
Faculty/School/Research Centre/Department > College of Health and Biomedicine
Depositing User: VUIR
Date Deposited: 04 Dec 2013 00:00
Last Modified: 28 Jan 2015 00:25
URI: http://vuir.vu.edu.au/id/eprint/22450
DOI: 10.1007/s10585-012-9553-6
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Citations in Scopus: 3 - View on Scopus

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