Identification of the Molecular Determinants of Breast Epithelial Cell Polarity

Establishment of polarity is indispensable for normal glandular function. Conversely, loss of tissue polarity and increased growth are hallmarks of tumorigenesis. Many studies indicate that cell-cell and cell-extracellular matrix interactions are involved in regulation of both cell polarity and growth. Tight junctions, which are the most apical components of cell-cell junctional complexes, play critical roles in the establishment of polarity. However, the molecular pathways that integrate these adhesive interactions to establish tissue polarity remain largely unresolved. A three dimensional laminin-rich extracellular matrix assay system using the HMT-3522 human breast tumor progression series is a good model to address how normal organ structure and function are maintained and how the balance is lost in cancer under physiologically relevant conditions. Using this assay system, I have investigated tight junction components and potential polarity regulator Rap1 which is the Ras superfamily small-G protein. Inhibiting Rap1 in malignant cells induces reversion to polarized acinus-like architecture from disorganized cell clusters. Further activation of Rap1 in malignant cells does not increase colony sizes or proliferation rate compared to control however, it enhances the resistance for reversion by inhibitors against EGFR or MEK. Rap1 activity also regulates several aspects of malignancy of breast cancer cells.