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Breast Cancer Research
Published in: Breast Cancer Research 2/2009

Open Access 01-04-2009 | Research article

Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms

Authors: Rachael A Hancox, Michael D Allen, Deborah L Holliday, Dylan R Edwards, Caroline J Pennington, David S Guttery, Jacqueline A Shaw, Rosemary A Walker, J Howard Pringle, J Louise Jones

Published in: Breast Cancer Research | Issue 2/2009

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Abstract

Introduction

The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms – one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16).

Methods

The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms.

Results

TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC up-regulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms.

Conclusions

These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms.
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Metadata
Title
Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms
Authors
Rachael A Hancox
Michael D Allen
Deborah L Holliday
Dylan R Edwards
Caroline J Pennington
David S Guttery
Jacqueline A Shaw
Rosemary A Walker
J Howard Pringle
J Louise Jones
Publication date
01-04-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2251

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