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Regulation of epithelial cell polarity during carcinogenesis

Pathogenesis of cancer begins as hyperplastic lesions; some lesions remain benign, while others progress to malignancy. An increase in cell proliferation rates and changes in tissue architecture are two properties commonly observed in hyperplastic lesions. A great deal is known about the molecular events that regulate cell proliferation and the knowledge gained is widely used for development of diagnostic and treatment tools. Our understanding of the mechanisms that deregulate tissue architecture is poor, and hence it is understandable that the use of architectural features to determine prognosis of early lesions has varying success. We used polarized epithelial cells and an inducible method of ErbB2 activation to investigate whether the cell architecture influences ErbB2-induced gene expression and to investigate how activation of ErbB2 disrupts epithelial cell architecture. Activation of ErbB2 in three-dimensional epithelial acini-like structures leads to expression of a unique set of genes that was not observed when ErbB2 was activated in cells grown on plastic dishes, suggesting that the cell architecture can have significant influence on ErbB2-induced gene expression. To investigate the effect of ErbB2 activation on epithelial architecture, we activated ErbB2 in polarized epithelial cells. ErbB2 induced a loss in apical–basal polarity, re-initiated proliferation and induced multilayering of epithelial sheets. These changes correlate with the ability of ErbB2 to regulate the Par complex, a protein complex known to regulate establishment of epithelial cell polarity. Inactivation of atypical protein kinase C, a component of the Par complex, cooperates with ErbB2 to disrupt polarized epithelial cells, suggesting that the Par complex is a mediator of ErbB2-induced effects on polarized epithelial cells. In addition, we identify tricellular junctions, and not bicellular junctions, as a novel site for ErbB2 action in cultured epithelial cells and in primary breast cancer. We are thus beginning to gain novel insights into the molecular mechanisms that regulate early lesions.

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Muthuswamy, S. Regulation of epithelial cell polarity during carcinogenesis. Breast Cancer Res 7 (Suppl 2), S.19 (2005).

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