Details

Autor(en) / Beteiligte

• Oudin, Madeleine J.
• Hughes-Alford, Shannon K.
• Miller, Miles
• Asokan, Sreeja B.
• Bear, James E.
• Lauffenburger, Doug A.
• Gertler, Frank B.

Titel

Abstract C41: MenaINV dysregulation of receptor tyrosine kinase signaling

Ist Teil von

• Cancer research (Chicago, Ill.), 2013-02, Vol.73 (3_Supplement), p.C41-C41

Erscheinungsjahr

2013

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Mena, an actin regulatory protein, is upregulated in human breast cancer and its expression is associated with increased metastatic progression. An invasion-specific isoform, MenaINV, is upregulated selectively in invasive tumor cells and increases invasion and metastasis by potentiating tumor cell responses to EGF. MenaINV causes dysregulation of the tyrosine phosphatase PTP1B, leading to increased phosphorylation of EGFR and other downstream targets. We investigated whether MenaINV could similarly promote invasion through dysregulation of signaling downstream of other receptor tyrosine kinases (RTKs). The behavior of MDA-MB-231 triple negative breast cancer cells stably expressing MenaINV or the other cannonical, broadly expressed Mena lacking the “INV” exon was measured after growth factor treatment in two migration assays: a 2D protrusion assay on matrigel and collagen coated coverslips and a 3D invasion assay into collagen gels. We found that expression of MenaINV sensitized responses to other EGFR ligands including HB-EGF and amphiregulin. In addition, MenaINV expression enhanced responses mediated by two other RTKs associated with tumor progression, Met and IGFR, both known PTP1B substrates. Cells expressing MenaINV respond to 20-fold lower concentrations HGF and IGF than control cells. However, there was no effect of MenaINV on responses to the ERBB3 ligand neuregulin and the chemokine SDF-1. Recently we reported that Mena can regulate cell motility in fibroblasts via its interaction with α5β1 integrin, which is known to co-traffic with EGFR and other RTKs to regulate invasion in tumor cells expressing mutant p53 or upon inhibition of αvβ3. We asked whether the direct interaction of Mena with α5β1 also contributes to invasion. Disrupting the interaction between the Mena isoforms and α5β1 in MDA-MB-231 cells affected how cells responded to EGF in a 3D collagen gel. In addition, fibroblasts that were null for Mena were unable to respond to a fibronectin gradient in a haptotaxis assay. Overall, these results suggest that the effects of MenaINV on invasion and metastasis could be mediated via different RTKs, as well as through direct interaction with integrins and the extracellular matrix. Experiments are currently underway to investigate how MenaINV regulates signalling downstream of these RTKs and integrins, to understand the molecular mechanism underlying the pro-metastatic effect of MenaINV. Citation Format: Madeleine J. Oudin, Shannon K. Hughes-Alford, Miles Miller, Sreeja B. Asokan, James E. Bear, Doug A. Lauffenburger, Frank B. Gertler. MenaINV dysregulation of receptor tyrosine kinase signaling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C41.