The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells

Yiling Lu, Yue Zhen Lin, Ruth LaPushin, Bruce Cuevas, Xianjun Fang, Shuang Xing Yu, Michael A. Davies, Humera Khan, Tatsuro Furui, Muling Mao, Ralph Zinner, Mien Chi Hung, Peter Steck, Kathy Siminovitch, Gordon Mills

Research output: Contribution to journalArticle

248 Citations (Scopus)

Abstract

The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in multiple types of sporadic tumors including breast cancers and also in the germline of patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene encodes a multifunctional phosphatase capable of dephosphorylating the same sites in membrane phosphatidylinositols phosphorylated by phosphatidylinositol 3'-kinase (P13K). We demonstrate herein that loss of PTEN function in breast cancer cells results in an increase in basal levels of phosphorylation of multiple components of the P13K signaling cascade as well as an increase in duration of ligand-induced signaling through the P13K cascade. These alterations are reversed by wild-type but not phosphatase inactive PTEN. In the presence of high concentrations of serum, enforced expression of PTEN induces a predominant G1 arrest consistent with the capacity of PTEN to evoke increases in the expression of the p27Kip1 cyclin dependent kinase inhibitor. In the presence of low concentrations of serum, enforced PTEN expression results in a marked increase in cellular apoptosis, a finding which is consistent with the capacity of PTEN to alter the phosphorylation, and presumably function, of the AKT, BAD, p70S6 kinase and GSK3α apoptosis regulators. Under anchorage-independent conditions, PTEN also induces anoikis, a form of apoptosis that occurs when cells are dissociated from the extracellular matrix, which is enhanced in conjunction with low serum culture conditions. Together, these data suggest that PTEN effects on the P13K signaling cascade are influenced by the cell stimulatory context, and that depending on the exposure to growth factors and other exogenous stimuli such as integrin ligation, PTEN can induce cell cycle arrest, apoptosis or anoikis in breast cancer cells.

Original languageEnglish (US)
Pages (from-to)7034-7045
Number of pages12
JournalOncogene
Volume18
Issue number50
StatePublished - Nov 25 1999
Externally publishedYes

Fingerprint

Anoikis
Tumor Suppressor Genes
Apoptosis
Breast Neoplasms
Growth
Serum
Phosphorylation
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinase
Cyclin-Dependent Kinases
Phosphatidylinositols
Cell Cycle Checkpoints
Phosphoric Monoester Hydrolases
Integrins
Extracellular Matrix
Ligation
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Ligands
Membranes

Keywords

  • Anoikis
  • Apoptosis
  • Breast cancer
  • Cell cycle arrest
  • PI3-k (phosphatidylinositol 3-kinase)
  • PTEN/MMAC1

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Lu, Y., Lin, Y. Z., LaPushin, R., Cuevas, B., Fang, X., Yu, S. X., ... Mills, G. (1999). The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 18(50), 7034-7045.

The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. / Lu, Yiling; Lin, Yue Zhen; LaPushin, Ruth; Cuevas, Bruce; Fang, Xianjun; Yu, Shuang Xing; Davies, Michael A.; Khan, Humera; Furui, Tatsuro; Mao, Muling; Zinner, Ralph; Hung, Mien Chi; Steck, Peter; Siminovitch, Kathy; Mills, Gordon.

In: Oncogene, Vol. 18, No. 50, 25.11.1999, p. 7034-7045.

Research output: Contribution to journalArticle

Lu, Y, Lin, YZ, LaPushin, R, Cuevas, B, Fang, X, Yu, SX, Davies, MA, Khan, H, Furui, T, Mao, M, Zinner, R, Hung, MC, Steck, P, Siminovitch, K & Mills, G 1999, 'The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells', Oncogene, vol. 18, no. 50, pp. 7034-7045.
Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene. 1999 Nov 25;18(50):7034-7045.
Lu, Yiling ; Lin, Yue Zhen ; LaPushin, Ruth ; Cuevas, Bruce ; Fang, Xianjun ; Yu, Shuang Xing ; Davies, Michael A. ; Khan, Humera ; Furui, Tatsuro ; Mao, Muling ; Zinner, Ralph ; Hung, Mien Chi ; Steck, Peter ; Siminovitch, Kathy ; Mills, Gordon. / The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. In: Oncogene. 1999 ; Vol. 18, No. 50. pp. 7034-7045.
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abstract = "The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in multiple types of sporadic tumors including breast cancers and also in the germline of patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene encodes a multifunctional phosphatase capable of dephosphorylating the same sites in membrane phosphatidylinositols phosphorylated by phosphatidylinositol 3'-kinase (P13K). We demonstrate herein that loss of PTEN function in breast cancer cells results in an increase in basal levels of phosphorylation of multiple components of the P13K signaling cascade as well as an increase in duration of ligand-induced signaling through the P13K cascade. These alterations are reversed by wild-type but not phosphatase inactive PTEN. In the presence of high concentrations of serum, enforced expression of PTEN induces a predominant G1 arrest consistent with the capacity of PTEN to evoke increases in the expression of the p27Kip1 cyclin dependent kinase inhibitor. In the presence of low concentrations of serum, enforced PTEN expression results in a marked increase in cellular apoptosis, a finding which is consistent with the capacity of PTEN to alter the phosphorylation, and presumably function, of the AKT, BAD, p70S6 kinase and GSK3α apoptosis regulators. Under anchorage-independent conditions, PTEN also induces anoikis, a form of apoptosis that occurs when cells are dissociated from the extracellular matrix, which is enhanced in conjunction with low serum culture conditions. Together, these data suggest that PTEN effects on the P13K signaling cascade are influenced by the cell stimulatory context, and that depending on the exposure to growth factors and other exogenous stimuli such as integrin ligation, PTEN can induce cell cycle arrest, apoptosis or anoikis in breast cancer cells.",
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