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- W1976635149 abstract "Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLThe Partitioning defective (Par) proteins are part of an evolutionarily conserved complex that is known to regulate asymmetric cell division, cell junction biogenesis and epithelial morphogenesis, but the role they play in cancer is not well understood. Here we demonstrate that loss of Partitioning defective 3 (Par3) cooperates with activation of the receptor tyrosine kinase ErbB2 to induce migration and invasion of normal and tumor-derived human mammary epithelial cells. Surprisingly, the acquisition of invasive ability was not associated with an overt mesenchymal transition as determined by a lack of expression of mesenchymal markers and retention of an epithelial morphology. We demonstrate that loss of Par3 induces aberrant activation of the small GTP binding protein Rac, loss of cortical actin and a decrease in cell-cell adhesion. Par3 is known to interact with and inhibit the Rac exchange factor Tiam1, consistently, ectopic expression of Tiam1 phenocopied Par3 loss and was sufficient to cooperate with ErbB2 to induce invasion and a decrease in intercellular adhesion. Inhibition of Tiam1-induced Rac activation restores cortical actin network and cell-cell junctions and blocks ErbB2-induced migration and invasion. Expression of Par3 was downregulated in both human breast cancer and in the metastasis resulting from ErbB2-expressing primary mouse mammary tumors. Forced downregulation of Par3 in ErbB2-tumor-derived primary epithelial cells promoted metastasis in vivo demonstrating that loss of Par3 is sufficient to initiate metastatic progression of ErbB2-induced mammary tumors. Thus, loss of Par3 induces metastatic properties to epithelial cells while expression of Par3 is required to maintain a non-metastatic epithelial state of tumor cells. Our observations on metastatic epithelia identify a novel mechanism by which tumor cells metastasize while retaining epithelial characteristics.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4037. doi:10.1158/1538-7445.AM2011-4037" @default.
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- W1976635149 date "2011-04-15" @default.
- W1976635149 modified "2023-09-25" @default.
- W1976635149 title "Abstract 4037: Loss of Par3 induces an epithelial to metastatic-epithelial transition during ErbB2 induced mammary tumor progression" @default.
- W1976635149 doi "https://doi.org/10.1158/1538-7445.am2011-4037" @default.
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