Pten suppresses breast cancer cell growth by phosphatase activity- dependent arrest followed by cell death

Liang Ping Weng, Wendy M. Smith, Patricia L.M. Dahia, Ulrike Ziebold, Elad Gil, Jacqueline A. Lees, Charis Eng

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Abstract

PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variety of human cancers. Germ-line mutations of phosphatase and tensin homolog, deleted on chromosome ten (PTEN) are found in two inherited hamartoma tumor syndromes: Cowden syndrome, which has a high risk of breast, thyroid, and other cancers; and Bannayan-Zonana syndrome, a related disorder. PTEN encodes a phosphatase that recognizes both protein substrates and phosphatidylinositol-3,4,5-triphosphate. The lipid phosphatase activity of PTEN seems to be important for growth suppression through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. We established clones with stable PTEN expression controlled by a tetracycline-inducible system to examine the consequences of increased levels of wild-type and mutant PTEN expression in a well-characterized breast cancer line, MCF-7. When we overexpressed PTEN in MCF-7, growth suppression was observed, but only if PTEN phosphatase activity is preserved. The initial growth suppression was attributable to G1 cell cycle arrest, whereas subsequent growth suppression was attributable to a combination of G1 arrest and cell death. Of note, the decrease in Akt phosphorylation preceded the onset of suppression of cell growth. Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused cell growth inhibition in a way similar to the effects of overexpression of PTEN in this cell. In general, the inverse correlation between PTEN protein level and Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore, PTEN appears to suppress breast cancer growth through down-regulating PI3K signaling, which leads to the blockage of cell cycle progression and the induction of cell death, in a sequential manner.

Original languageEnglish (US)
Pages (from-to)5808-5814
Number of pages7
JournalCancer Research
Volume59
Issue number22
StatePublished - Nov 15 1999

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Weng, L. P., Smith, W. M., Dahia, P. L. M., Ziebold, U., Gil, E., Lees, J. A., & Eng, C. (1999). Pten suppresses breast cancer cell growth by phosphatase activity- dependent arrest followed by cell death. Cancer Research, 59(22), 5808-5814.