Tumor cell invasion into the surrounding stroma requires increased cell motility and extensive remodeling of the extracellular matrix.
Endo180 (CD280, MRC2,
urokinase-type plasminogen activator receptor-associated
protein) is a recycling endocytic receptor that functions in both these cellular activities by promoting cell migration and uptake of
collagens for intracellular degradation. In the normal breast,
Endo180 is predominantly expressed by stromal fibroblasts. The contrary observation that
Endo180 is expressed on epithelial tumor cell lines that display a high invasive capacity suggested that up-regulation of this receptor may be an associated and functional component in the acquisition of a more aggressive phenotype by
tumor cells in vivo. Here, we show that high levels of
Endo180 are found in a subset of basal-like breast
cancers and that this expression is an independent prognostic marker for shorter disease-free survival. Two potential mechanisms for
Endo180 up-regulation were uncovered. First, it was shown that
Endo180 can be transcriptionally up-regulated in vitro following
transforming growth factor-beta treatment of
breast cancer cells. Second, a proportion of
Endo180(+)
tumors were shown to have
Endo180 gene copy number gains and amplifications. To investigate the functional consequence of
Endo180 up-regulation, MCF7 cells transfected with
Endo180 were inoculated into immunocompromised mice. Expression of wild-type
Endo180, but not an internalization-defective
Endo180 mutant, resulted in enhanced
tumor growth together with a reduction in
tumor collagen content. Together, these data argue that elevated expression of this receptor in
tumor cells could have important consequences in subsets of basal-like
carcinomas for which there is a current lack of effective treatment.