Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4134-9. doi: 10.1073/pnas.0511342103. Epub 2006 Mar 7.

Abstract

Akt1 is frequently up-regulated in human tumors and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibition of the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depend on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / physiopathology
  • Breast Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Focal Adhesions
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Neoplasm Transplantation
  • Oncogenes
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / physiology*
  • Transplantation, Heterologous
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology*
  • rho GTP-Binding Proteins / antagonists & inhibitors

Substances

  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • rho GTP-Binding Proteins