Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The overall goal of the work was to better understand the mechanisms through which podocalyxin increases cancer aggressiveness. Over-expression of podocalyxin in human breast and prostate cancer cell-lines led to increased invasive and migratory potential in vitro, increased expression of matrix metalloproteases (MMPs), and increased MAPK and PI3K activity. Importantly, the ability of podocalyxin to increase MAPK and PI3K activity, MMP expression, as well as cellular migration and invasion was found to be dependent on the formation of a complex containing podocalyxin and the metastasis promoting protein ezrin. Transient knockdown of ezrin protein abrogated the aggressive phenotype of cancer cells over-expressing podocalyxin.
Podocalyxin protein expression also correlated with measures of cancer aggressiveness in breast cancer tissue microarrays. Expression of podocalyxin correlated with high Bloom Richardson Grade, expression of the basal-like breast cancer subtype-associated protein fascin, and development of brain metastases. To test the hypothesis that podocalyxin expression correlated with the more aggressive basal-like subtype of breast cancers, podocalyxin was stably over-expressed in luminal-like breast cancer cell lines. Stable expression of podocalyxin in luminal-like breast cancer cells resulted in a concomitant decrease in expression of luminal-subtype associated markers and increased expression of basal-subtype associated markers. Together these data advance our understanding of the development of aggressive, metastatic cancers and suggest novel diagnostic and therapeutic options for cancer treatment.