LPP is Required for TGF-Beta Induced Motility and Invasion of Neu/ErbB-2 Expressing Breast Cancer Cells

Abstract

Abstract : Overexpression of the ErbB2 receptor tyrosine kinase is associated with metastatic breast cancer progression and is correlated with poor patient prognosis. Numerous cell-based and transgenic mouse models have demonstrated that ErbB2 and TGF Beta signaling cooperatively promote breast cancer cell aggressiveness and metastasis. Nonetheless, the mechanisms underlying the synergy between these two pathways remain unclear. In the present study, we demonstrate that Lipoma Preferred Partner (LPP) is indispensable for mediating TGF Beta - induced cell migration and invasion of ErbB2 expressing breast cancer cells. Furthermore, we show that focal adhesion targeting of LPP, through its LIM1 domain, is required for the migratory and invasive phenotypes of ErbB2 positive breast cancer cells in response to TGF Beta. Using Fluorescence Recovery After Photobleaching (FRAP) techniques, we also determined that LPP is a critical determinant in TGF - mediated focal adhesion dynamics and turnover of ErbB2 expressing mammary tumor cells. Together, we have identified LPP as a novel mediator that integrates TGF Beta and ErbB2 signaling to promote the migration and invasion of breast cancer cells. Thus, we have further uncovered the mechanisms underlying the synergy between TGF Beta and ErbB2 signaling pathways to enhance breast cancer metastasis.