Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.

The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to...

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Autores principales:	Jeffrey J Wallin, Jane Guan, Kyle A Edgar, Wei Zhou, Ross Francis, Anthony C Torres, Peter M Haverty, Jeffrey Eastham-Anderson, Sabrina Arena, Alberto Bardelli, Sue Griffin, John E Goodall, Kyla M Grimshaw, Klaus P Hoeflich, Christopher Torrance, Marcia Belvin, Lori S Friedman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64952bf9ee0a4f75af0606c666386285
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spelling	oai:doaj.org-article:64952bf9ee0a4f75af0606c6663862852021-11-18T07:19:48ZActive PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.1932-620310.1371/journal.pone.0036402https://doaj.org/article/64952bf9ee0a4f75af0606c6663862852012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22570710/?tool=EBIhttps://doaj.org/toc/1932-6203The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.Jeffrey J WallinJane GuanKyle A EdgarWei ZhouRoss FrancisAnthony C TorresPeter M HavertyJeffrey Eastham-AndersonSabrina ArenaAlberto BardelliSue GriffinJohn E GoodallKyla M GrimshawKlaus P HoeflichChristopher TorranceMarcia BelvinLori S FriedmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e36402 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jeffrey J Wallin Jane Guan Kyle A Edgar Wei Zhou Ross Francis Anthony C Torres Peter M Haverty Jeffrey Eastham-Anderson Sabrina Arena Alberto Bardelli Sue Griffin John E Goodall Kyla M Grimshaw Klaus P Hoeflich Christopher Torrance Marcia Belvin Lori S Friedman Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
description	The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.
format	article
author	Jeffrey J Wallin Jane Guan Kyle A Edgar Wei Zhou Ross Francis Anthony C Torres Peter M Haverty Jeffrey Eastham-Anderson Sabrina Arena Alberto Bardelli Sue Griffin John E Goodall Kyla M Grimshaw Klaus P Hoeflich Christopher Torrance Marcia Belvin Lori S Friedman
author_facet	Jeffrey J Wallin Jane Guan Kyle A Edgar Wei Zhou Ross Francis Anthony C Torres Peter M Haverty Jeffrey Eastham-Anderson Sabrina Arena Alberto Bardelli Sue Griffin John E Goodall Kyla M Grimshaw Klaus P Hoeflich Christopher Torrance Marcia Belvin Lori S Friedman
author_sort	Jeffrey J Wallin
title	Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
title_short	Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
title_full	Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
title_fullStr	Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
title_full_unstemmed	Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
title_sort	active pi3k pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/64952bf9ee0a4f75af0606c666386285
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Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.

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