Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices

Raviraj, Vanisri, Fok, Sandra, Zhao, Jifei, Chien, Hsin-Ya, Lyons, J. Guy, Thompson, Erik W., & Soon, Lilian (2012) Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices. BMC Cell Biology, 13(12).

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Abstract

Background

The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated.

Results

We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275.

Conclusion

Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.

Impact and interest:

13 citations in Scopus
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13 citations in Web of Science®

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ID Code: 71723
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By (since 1996):4
Export Date: 6 May 2014
Source: Scopus
Art. No.: 12
PubMed ID: 22583596
Additional URLs:
Keywords: Breast cancer, Cancer cell migration, High-density matrix, Histone deacetylase inhibitors, ROCK expression
DOI: 10.1186/1471-2121-13-12
ISSN: 1471-2121
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2012 Raviraj et al.; licensee BioMed Central Ltd.
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Deposited On: 16 May 2014 03:16
Last Modified: 19 May 2014 01:33

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