A Role for the Polarity Protein Par3 in ErbB2-induced Breast Cancer
The Graduate School, Stony Brook University: Stony Brook, NY.
Polarity protein Partitioning defective protein 3 (Par3) is an evolutional conserved scaffold protein in metazoans. Par3 together with Par6 and aPKC form Par complex and localize at the subapical domain of epithelial cells. Par3 plays important roles during establishment of apical membrane and tight junctions in epithelia. In my thesis, I identified Par3 as a novel metastasis suppressor in breast cancer. ErbB2, also known as HER2, is an important proto-oncogene in breast cancer. Approximately 25% of breast cancers have ErbB2 amplification or overexpression and correlate with poor prognosis. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion in mammary epithelial cells in vitro and induced metastasis of ErbB2-induced primary mouse mammary tumors. Surprisingly, loss of Par3 induced invasive behavior in the epithelial cells was not associated with an overt epithelial mesenchymal transition. However, loss of Par3 prevented E-cadherin junction maturation and decreased cell-cell cohesion. I identified the molecular mechanisms by which Par3 regulates E-cadherin junction maturation. Downregulation of Par3 induced spatial and temporal dysregulation of Rac activation by activating Rac-GEF Tiam1. In addition I found Par3 interacted with a branched actin polymerizing protein complex, Arp2/3 and assembles an E-cadherin-Par3-Arp2/3 at cell-cell junctions. Loss of Par3 resulted in mislocalization of Arp2/3 from cell-cell junctions. The aberrant Rac activation and disruption of Arp2/3 from cell-cell junctions induced aberrant actin cytoskeleton organization at cell-cell junctions that resulted in inhibition of maturation on E-cadherin junctions. In human breast cancer, decrease in membrane Par3 was correlated with higher tumor grade and ErbB2 positive status. Dysregulation of Par3 was found in the metastases compared to the primary breast tumors. Together, our data suggest that loss of Par3 promotes metastatic behavior of ErbB2-induced tumor epithelial cells by decreasing cell-cell cohesion.