Type 1 Insulin-Like Growth Factor Receptor/Insulin Receptor Substrate 1 Signaling Confers Pathogenic Activity on Breast Tumor Cells Lacking REST.

Abstract

Loss of repressor element 1 silencing transcription factor (REST) occurs in 20% of breast cancers and correlates with a poor patient prognosis. However, the molecular basis for enhanced malignancy in tumors lacking REST (RESTless) is only partially understood. We used multiplatform array data from the Cancer Genome Atlas to identify consistent changes in key signaling pathways. Of the proteins screened in the reverse-phase protein array, we found that insulin receptor substrate 1 (IRS1) is the most highly upregulated protein in RESTless breast tumors. Analysis of breast tumor cell lines showed that REST directly represses IRS1, and cells lacking REST have increased levels of IRS1 mRNA and protein. We find that the upregulation of IRS1 function is both necessary and sufficient for enhanced signaling and growth in breast cancer cells lacking REST. IRS1 overexpression is sufficient to phenocopy the enhanced activation of the signaling hubs AKT and mitogen-activated protein kinase (MAPK) of MCF7 cells lacking REST. Loss of REST renders MCF7 and MDA-MB-231 breast tumor cells dependent on IRS1 activity for colony formation in soft agar. Inhibition of the type 1 insulin-like growth factor receptor (IGF1R) reduces the enhanced signaling, growth, and migration in breast tumor cells that occur upon REST loss. We show that loss of REST induces a pathogenic program that works through the IGF1R/IRS1 pathway.

• Authors: Kassondra Meyer, Brittany Albaugh, Barry Schoenike, Avtar Roopra
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 17 Pg. 2991-3004 (Sep 01 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 26100015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• IGF1R protein, human
• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• Phosphoinositide-3 Kinase Inhibitors
• RE1-silencing transcription factor
• RNA, Small Interfering
• Receptors, Somatomedin
• Repressor Proteins
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinases

Topics

• Breast Neoplasms (genetics, mortality, pathology)
• Cell Line, Tumor
• Cell Movement
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Female
• Humans
• Insulin Receptor Substrate Proteins (biosynthesis, genetics, metabolism)
• MAP Kinase Signaling System (genetics)
• MCF-7 Cells
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• RNA, Small Interfering
• Receptor, IGF Type 1
• Receptors, Somatomedin (antagonists & inhibitors, genetics, metabolism)
• Repressor Proteins (genetics)