The expression and distribution of Tenascin C in breast cancer invasion
Tenascin C (TNC) is an extracellular matrix protein that is expressed at low levels in normal adult tissue but is highly expressed around breast cancers. TNC exists as multiple isoforms generated through alternative splicing. Isoform expression in benign and malignant breast disease was investigated.;Significant differences in TNC isoform profile were identified. Whilst all tissues expressed the fully truncated TNC, expression of two additional isoforms was significantly associated with the invasive phenotype (p<0.001). A subset of pre-invasive carcinomas also expressed these additional isoforms. Furthermore, expression correlated with the presence of additional protein isoforms in stroma, where they were produced by stromal fibroblasts in malignant tissue, and both periductal fibroblasts and residual myoepithelial cells in ductal carcinoma in-situ (DCIS).;In-vitro experiments indicated growth factor specific induction of TNC. Epidermal growth factor induced expression of higher molecular weight TNC isoforms but initial investigations with transforming growth factor beta1 had no effect.;Two highly invasive breast cancer cell lines (MDA-MB 231 and MDA-MB 468) were found to produce TNC in contrast to tumour cells with a lower invasive capacity (MCF7 and T47D). TNC altered cell morphology and increased migration in cell lines MCF7, T47D and MDA-MB 468, but not MDA-MB 231. Effects on migration via alteration in fibroblast function was also seen in cell lines MCF7, T47D, and MDA-MB 468 , but not cell line MDA-MB 231. This indicates cell type specific direct and indirect effects of TNC on migration.;TNC had no effect on proliferation, or on the expression of a range of matrix metalloproteinases associated with breast carcinoma.;Primary tissue analysis demonstrates for the first time that specific TNC isoforms are expressed in invasive breast carcinomas and that these isoforms are identified in a subset of DCIS. These isoforms may predict invasion and thus provide, appropriate targets for therapeutic intervention.