Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase

Huan Pang, Rory Flinn, Antonia Patsialou, Jeffrey Wyckoff, Evanthia T. Roussos, Haiyan Wu, Maria Pozzuto, Sumanta Goswami, John S. Condeelis, Anne R. Bresnick, Jeffrey E. Segall, Jonathan M. Backer

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Class IA (p85/p110) phosphoinositide 3-kinases play a major role in regulating cell growth, survival, and motility. Activating mutations in the p110α isoform of the class IA catalytic subunit (PIK3CA) are commonly found in human cancers. These mutations lead to increased proliferation and transformation in cultured cells, but their effects on cell motility and tumor metastasis have not been evaluated. We used lentiviral-mediated gene transfer and knockdown to produce stable MDA-MB-231 cells in which the endogenous human p110α is replaced with either wild-type bovine p110α or the two most common activating p110α mutants, the helical domain mutant E545K and the kinase domain mutant H1047R. The phosphoinositide 3-kinase/Akt pathway was hyperactivated in cells expressing physiologic levels of helical or kinase domain mutants. Cells expressing either mutant showed increased motility in vitro, but only cells expressing the helical domain mutant showed increased directionality in a chemotaxis assay. In severe combined immunodeficient mice, xenograft tumors expressing either mutant showed increased rates of tumor growth compared with tumors expressing wild-type p110α. However, tumors expressing the p110α helical domain mutant showed a marked increase in both tumor cell intravasation into the blood and tumor cell extravasation into the lung after tail vein injection compared with tumors expressing wild-type p110α or the kinase domain mutant. Our observations suggest that, when compared with kinase domain mutations in a genetically identical background, expression of helical domain mutants of p110α produce a more severe metastatic phenotype.

Original languageEnglish (US)
Pages (from-to)8868-8876
Number of pages9
JournalCancer Research
Volume69
Issue number23
DOIs
StatePublished - Dec 1 2009

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1-Phosphatidylinositol 4-Kinase
Cell Movement
Phosphotransferases
Breast Neoplasms
Neoplasm Metastasis
Mutation
Neoplasms
Gene Knockdown Techniques
IA 3
SCID Mice
Chemotaxis
Growth
Heterografts
Tail
Veins
Cultured Cells
Blood Cells
Catalytic Domain
Cell Survival
Protein Isoforms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. / Pang, Huan; Flinn, Rory; Patsialou, Antonia; Wyckoff, Jeffrey; Roussos, Evanthia T.; Wu, Haiyan; Pozzuto, Maria; Goswami, Sumanta; Condeelis, John S.; Bresnick, Anne R.; Segall, Jeffrey E.; Backer, Jonathan M.

In: Cancer Research, Vol. 69, No. 23, 01.12.2009, p. 8868-8876.

Research output: Contribution to journalArticle

Pang, Huan ; Flinn, Rory ; Patsialou, Antonia ; Wyckoff, Jeffrey ; Roussos, Evanthia T. ; Wu, Haiyan ; Pozzuto, Maria ; Goswami, Sumanta ; Condeelis, John S. ; Bresnick, Anne R. ; Segall, Jeffrey E. ; Backer, Jonathan M. / Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. In: Cancer Research. 2009 ; Vol. 69, No. 23. pp. 8868-8876.
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AU - Roussos, Evanthia T.

AU - Wu, Haiyan

AU - Pozzuto, Maria

AU - Goswami, Sumanta

AU - Condeelis, John S.

AU - Bresnick, Anne R.

AU - Segall, Jeffrey E.

AU - Backer, Jonathan M.

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