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

Hong Liu, Derek C Radisky, Celeste M. Nelson, Hui Zhang, Jimmie E. Fata, Richard A. Roth, Mina J. Bissell

Research output: Contribution to journalArticle

137 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4134-4139
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number11
DOIs
StatePublished - Mar 14 2006

Fingerprint

Tuberous Sclerosis
Breast Neoplasms
Oncogenes
Neoplasm Metastasis
Neoplasms
Stress Fibers
rho GTP-Binding Proteins
Focal Adhesions
Tumor Suppressor Genes
Genes
Actins
Cell Death
Epithelium
Cell Proliferation
Phenotype
Survival
Therapeutics
Inhibition (Psychology)
Tuberous Sclerosis 2

Keywords

  • Metastasis
  • Oncogene
  • Tumor suppressor

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. / Liu, Hong; Radisky, Derek C; Nelson, Celeste M.; Zhang, Hui; Fata, Jimmie E.; Roth, Richard A.; Bissell, Mina J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 11, 14.03.2006, p. 4134-4139.

Research output: Contribution to journalArticle

Liu, Hong ; Radisky, Derek C ; Nelson, Celeste M. ; Zhang, Hui ; Fata, Jimmie E. ; Roth, Richard A. ; Bissell, Mina J. / Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 11. pp. 4134-4139.
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