Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability.

Heregulin-beta1 (HRG) promotes motility, scattering, and invasiveness of breast cancer cells. Tiam1, a newly identified guanine nucleotide exchange factor, has been shown to inhibit or promote cell migration in a cell type-dependent manner. In this study, we identified Tiam1 as a target of HRG signaling. HRG stimulation of breast cancer epithelial cells induced the phosphorylation and redistribution of Tiam1 to the membrane ruffles and the loosening of intercellular junctions. In addition, HRG-mediated scattering of breast epithelial cells was accompanied by stimulation of tyrosine phosphorylation and redistribution of beta-catenin from the cell junctions to the cytosol and, finally, entry into the nucleus. Decompaction of breast cancer epithelial cells by HRG was accompanied by a transient physical association of the tyrosine-phosphorylated beta-catenin with the activated human epidermal growth factor receptor 2 and subsequent nuclear translocation of beta-catenin, as well as beta-catenin-dependent transactivation of T-cell factor.lymphoid enhancer factor-1. All of these HRG-induced phenotypic changes were regulated in a phosphatidylinositol-3 kinase-sensitive manner. HRG-induced cellular ruffles, loss of intercellular adhesiveness, and increased cell migration could be mimicked by overexpression of a fully functional Tiam1 construct. Furthermore, ectopic expression of Tiam1 or of an active beta-catenin mutant led to potentiation of the beta-catenin-dependent T-cell factor.lymphoid enhancer factor-1 transactivation and invasiveness of HRG-treated cells. We also found preliminary evidence suggesting a close correlation between the status of Tiam1 expression and invasiveness of human breast tumor cells with the degree of progression of breast tumors. Together, these findings suggest that HRG regulate Tiam1 activation and lymphoid enhancer factor/beta-catenin nuclear signaling via phosphatidylinositol-3 kinase in breast cancer cells.