NDLI: Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA PI3K

Content Provider	PubMed Central
Author	Pang, Huan Flinn, Rory Antonia, Patsialou Wyckoff, Jeffrey Roussos, Evanthia T. Wu, Haiyan Maria, Pozzutto Goswami, Sumanta Condeelis, John S. Bresnick, Anne R. Segall, Jeffrey E. Backer, Jonathan M.
Abstract	Class IA (p85/p110) PI 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 PI3K/Akt pathway was hyperactivated in cells expressing physiological 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 SCID mice, xenograft tumors expressing either mutant showed increased rates of tumor growth as compared to 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, as compared to tumors expressing wild type p110α or the kinase domain mutant. Our observations suggest that when compared to kinase domain mutations in a genetically identical background, expression of helical domain mutants of p110α produce a more severe metastatic phenotype.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-1968
Ending Page	8876
Page Count	9
Starting Page	8868
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	23
Volume Number	69
Language	English
Publisher Date	2009-12-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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