title: Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.
abstract: 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.
authors.affiliation: Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, California, USA. jwallin@gene.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Jane
authors.initials: J
authors.lastname: Guan
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Edgar
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Ross
authors.initials: R
authors.lastname: Francis
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Torres
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Sue
authors.initials: S
authors.lastname: Griffin
authors.forename: John E
authors.initials: JE
authors.lastname: Goodall
authors.forename: Kyla M
authors.initials: KM
authors.lastname: Grimshaw
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Christopher
authors.initials: C
authors.lastname: Torrance
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D004789:Enzyme Activation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C484760:PIK3CA protein, human