Role of TGF-β receptor III localization in polarity and breast cancer progression

The majority of breast cancers originate from the highly polarized luminal epithelial cells lining the breast ducts. However, cell polarity is often lost during breast cancer progression. The type III transforming growth factor-beta cell surface receptor (T beta RIII) functions as a suppressor of breast cancer progression and also regulates the process of epithelial-to-mesenchymal transition (EMT), a consequence of which is the loss of cell polarity. Many cell surface proteins exhibit polarized expression, being targeted specifically to the apical or basolateral domains. Here we demonstrate that T beta RIII is basolaterally localized in polarized breast epithelial cells and that disruption of the basolateral targeting of T beta RIII through a single amino acid mutation of proline 826 in the cytosolic domain results in global loss of cell polarity through enhanced EMT. In addition, the mistargeting of T beta RIII results in enhanced proliferation, migration, and invasion in vitro and enhanced tumor formation and invasion in an in vivo mouse model of breast carcinoma. These results suggest that proper localization of T beta RIII is critical for maintenance of epithelial cell polarity and phenotype and expand the mechanisms by which T beta RIII prevents breast cancer initiation and progression.