Abstract
Transforming growth factor β (TGFβ) is a potent modifier of the malignant phenotype in ErbB2-expressing breast cancers. We demonstrate that epithelial-derived breast cancer cells, which undergo a TGFβ-induced epithelial-to-mesenchymal transition (EMT), engage signaling molecules that normally facilitate cellular migration and invasion of mesenchymal cells. We identify lipoma preferred partner (LPP) as an indispensable regulator of TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. We show that LPP re-localizes to focal adhesion complexes upon TGFβ stimulation and is a critical determinant in TGFβ-mediated focal adhesion turnover. Finally, we have determined that the interaction between LPP and α-actinin, an actin cross-linking protein, is necessary for TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Thus, our data reveal that LPP, which is normally operative in cells of mesenchymal origin, can be co-opted by breast cancer cells during an EMT to promote their migration and invasion.
Keywords:
Breast cancer; EMT; ErbB2; Invasion; LPP; Migration; TGFβ.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actinin / genetics
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Actinin / metabolism*
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Movement*
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Female
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Gene Expression Regulation, Enzymologic*
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Gene Expression Regulation, Neoplastic*
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Humans
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LIM Domain Proteins / genetics
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LIM Domain Proteins / metabolism*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Neoplasm Invasiveness
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Receptor, ErbB-2 / biosynthesis*
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Receptor, ErbB-2 / genetics
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
Substances
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Cytoskeletal Proteins
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LIM Domain Proteins
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LPP protein, human
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Lpp protein, mouse
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Multiprotein Complexes
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Transforming Growth Factor beta
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Actinin
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ERBB2 protein, human
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Erbb2 protein, mouse
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Receptor, ErbB-2