Metastasis is the major cause of
cancer-related morbidity and mortality. The ability of
cancer cells to become invasive and migratory contribute significantly to metastatic growth, which necessitates the identification of novel anti-migratory and anti-invasive therapeutic approaches.
Proteoglycan 4 (PRG4), a
mucin-like
glycoprotein, contributes to joint synovial homeostasis through its friction-reducing and anti-adhesive properties. Adhesion to surrounding extracellular matrix (ECM) components is critical for
cancer cells to invade the ECM and eventually become metastatic, raising the question whether PRG4 has an anti-invasive effect on
cancer cells. Here, we report that a full-length recombinant human PRG4 (rhPRG4) suppresses the ability of the secreted
protein transforming growth factor beta (TGFβ) to induce phenotypic disruption of three-dimensional human
breast cancer cell-derived organoids by reducing
ligand-induced cell invasion. In mechanistic studies, we find that rhPRG4 suppresses TGFβ-induced invasiveness of
cancer cells by inhibiting the downstream
hyaluronan (HA)-cell surface cluster of differentiation 44 (CD44) signalling axis. Furthermore, we find that rhPRG4 represses TGFβ-dependent increase in the
protein abundance of CD44 and of the
enzyme HAS2, which is involved in HA biosynthesis. It is widely accepted that TGFβ has both
tumor suppressing and
tumor promoting roles in
cancer. The novel finding that rhPRG4 opposes HAS2 and CD44 induction by TGFβ has implications for downregulating the
tumor promoting roles, while maintaining the
tumor suppressive aspects of TGFβ actions. Finally, these findings point to rhPRG4's potential clinical utility as a therapeutic treatment for invasive and metastatic
breast cancer.