A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells

Arias-Romero, L. E., Villamar-Cruz, O., Pacheco, A., Kosoff, R., Huang, M., Muthuswamy, S. K., Chernoff, J. (October 2010) A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene, 29 (43). pp. 5839-49. ISSN 0950-9232

URL: http://www.ncbi.nlm.nih.gov/pubmed/20711231
DOI: 10.1038/onc.2010.318

Abstract

The activation of receptor tyrosine kinases, particularly ErbB2, has an important role in the genesis of breast cancer. ErbB2 kinase activity promotes Ras-mediated stimulation of downstream protein kinase cascades, including the Ras/Raf-1/MAPK/ERK kinase (Mek)/extracellular signal-regulated kinase (Erk) pathway, leading to tumor cell growth and migration. Signaling through the Ras-Erk pathway can be influenced by p21-activated kinase-1 (Pak1), an effector of the Rho family GTPases Rac and Cdc42. In this study, we asked if ErbB2 expression correlates with Pak1 and Erk activity in human breast cancer specimens, and if Pak1 signaling is required for ErbB2 transformation in a three-dimensional (3D) in vitro setting and in xenografts. We found a correlation between ErbB2 expression and activation of Pak in estrogen receptor-positive human breast tumor samples and observed that in 3D cultures, activation of Rac-Pak1 pathway by ErbB2 homodimers induced growth factor-independent proliferation and promoted disruption of 3D mammary acinar-like structures through activation of the Erk and Akt pathways. Further, we found that inhibition of Pak1 by small molecules compromised activation of Erk and Akt, resulting in reversion of the malignant phenotype and restoration of normal acinar architecture. Finally, ErbB2-amplified breast cancer cells expressing a specific Pak inhibitor showed delayed tumor formation and downregulation of Erk and Akt signaling in vivo. These data imply that the Rac-Pak pathway is vital to ErbB2-mediated transformation and that Pak inhibitors represent plausible drug targets in breast cancers in which ErbB2 signaling is activated.

Item Type: Paper
Uncontrolled Keywords: Animals Blotting, Western Breast Neoplasms/genetics/*metabolism/pathology Cell Line, Tumor Cell Proliferation/drug effects Cell Transformation, Neoplastic/drug effects/genetics/*metabolism Enzyme Inhibitors/pharmacology Extracellular Signal-Regulated MAP Kinases/genetics/metabolism Female Fluorescent Antibody Technique Humans Immunohistochemistry Mice Mice, SCID Proto-Oncogene Proteins c-akt/genetics/metabolism Receptor, ErbB-2/genetics/*metabolism Signal Transduction/drug effects/*physiology Tissue Array Analysis Xenograft Model Antitumor Assays p21-Activated Kinases/genetics/*metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > ErbB
diseases & disorders > cancer > cancer types > breast cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Muthuswamy lab
Depositing User: Matt Covey
Date: 28 October 2010
Date Deposited: 15 Oct 2015 16:48
Last Modified: 15 Oct 2015 16:48
PMCID: PMC2965784
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31926

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