MCT4 and CD147 co-localize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells.

The lactate-proton cotransporter MCT4 and its chaperone CD147 are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and CD147 favor breast cancer invasion through interdependent effects on extracellular matrix (ECM) degradation. MCT4 and CD147 expression and membrane localization were strongly reciprocally interdependent in MDA-MB-231 breast cancer cells. Knockdown (KD) and overexpression (OE) of MCT4 and/or CD174 in- and decreased, respectively, migration, invasion, and fluorescent gelatin degradation. OE of both proteins increased gelatin degradation and appearance of the matrix metalloprotease (MMP)-generated collagen-I cleavage product reC1M more than each protein alone, suggesting a concerted role in ECM degradation. MCT4 and CD147 co-localized with invadopodia markers at the plasma membrane and with MMP14, the lysosomal marker LAMP-1, and partially with the autophagosome marker LC3, in F-actin-decorated intracellular vesicles. We conclude that MCT4 and CD147 reciprocally regulate each other and interdependently support migration and invasiveness of MDA-MB-231 breast cancer cells. Mechanistically, this involves MCT4-CD147-dependent stimulation of ECM degradation and specifically of MMP-mediated collagen-I degradation. We suggest that the MCT4-CD147 complex is co-delivered to invadopodia with MMP14.