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A complex containing LPP and ?-actinin mediates TGF?-induced migration and invasion of ErbB2-expressing breast cancer cells.

ABSTRACT: Transforming growth factor ? (TGF?) is a potent modifier of the malignant phenotype in ErbB2-expressing breast cancers. We demonstrate that epithelial-derived breast cancer cells, which undergo a TGF?-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 TGF?-induced migration and invasion of ErbB2-expressing breast cancer cells. We show that LPP re-localizes to focal adhesion complexes upon TGF? stimulation and is a critical determinant in TGF?-mediated focal adhesion turnover. Finally, we have determined that the interaction between LPP and ?-actinin, an actin cross-linking protein, is necessary for TGF?-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.

SUBMITTER: Ngan E

PROVIDER: S-EPMC3791827 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A complex containing LPP and α-actinin mediates TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells.

Ngan Elaine E Northey Jason J JJ Brown Claire M CM Ursini-Siegel Josie J Siegel Peter M PM

Journal of cell science 20130227 Pt 9

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 ca ...[more]

PMID: 23447672

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Project description:Dickkopf-1 (DKK1), an inhibitor of the most frequently impaired signaling pathway in hepatocellular carcinoma (HCC), the Wnt/beta-catenin pathway, seems to fulfill contradictory functions in the process of tumorigenesis, acting either as an oncogenic promoter of metastasis or as a tumor suppressor. Elevated serum levels of DKK1 have been reported in HCC; however, little is known about its functional significance. In the current study, we treated HepG2/C3A and PLC/PRF/5 with the recombinant protein DKK1. Cytotoxicity was first determined by the WST-8 assay. AFP expression was measured at both the mRNA and protein levels. Expression of the oncogenes MYC, CCND1, hTERT, and MDM2 and the tumor suppressor genes TP53, P21 and RB was assessed. Western blot analysis of non-phosphorylated ?-catenin and Sanger sequencing were performed to explain the functional differences between the two cell lines. Subsequently, inflammation, migration and invasion were evaluated by qPCR, ELISA, the Boyden chamber assay, zymography, and MMP-2 and MMP-9 western blot analysis. Knockdown of DKK1 and TGF-?1 were also performed. Our results suggest that DKK1 exerts an oncogenic effect on HepG2/C3A cell line by upregulating the expression of oncogenes and downregulating that of tumor suppressor genes, whereas the opposite effect was demonstrated in PLC/PRF/5 cells. This differential impact of DKK1 can be explained by the mutations that affect the canonical Wnt pathway that were detected in exon 3 of the CTNNB1 gene in the HepG2 cell line. We further confirmed that DKK1 promotes inflammation, tumor invasion and migration in both cell types. The canonical pathway was not responsible for the DKK1 proinvasive effect, as indicated by the active ?-catenin levels in the two cell lines upon DKK1 treatment. Interestingly, knockdown of TGF-?1 negatively affected the DKK1 proinvasive effect. Taken together, DKK1 appears to facilitate tumor invasion and migration through TGF- ?1 by remodeling the tumor microenvironment and inducing inflammation. This finding endorses the relevance of TGF-?1 as a therapeutic target.

Dataset Information

A complex containing LPP and ?-actinin mediates TGF?-induced migration and invasion of ErbB2-expressing breast cancer cells.

Publications

A complex containing LPP and α-actinin mediates TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells.

Similar Datasets

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