title: Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer.
abstract: The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110α subunit account for activation of this pathway in 20% to 40% of cases, particularly in estrogen receptor alpha (ERα)-positive breast cancers. AKT family of kinases, AKT1-3, are the downstream targets of PI3K and these kinases activate ERα. Although several inhibitors of PI3K have been developed, none has proven effective in the clinic, partly due to an incomplete understanding of the selective routing of PI3K signaling to specific AKT isoforms. Accordingly, we investigated in this study the contribution of specific AKT isoforms in connecting PI3K activation to ERα signaling, and we also assessed the utility of using the components of PI3K-AKT isoform-ERα signaling axis as predictive biomarkers of response to PI3K inhibitors. Using a variety of physiologically relevant model systems with defined natural or knock-in PIK3CA mutations and/or PI3K hyperactivation, we show that PIK3CA-E545K mutations (found in ∼20% of PIK3CA-mutant breast cancers), but not PIK3CA-H1047R mutations (found in 55% of PIK3CA-mutant breast cancers), preferentially activate AKT1. Our findings argue that AKT1 signaling is needed to respond to estrogen and PI3K inhibitors in breast cancer cells with PIK3CA-E545K mutation, but not in breast cancer cells with other PIK3CA mutations. This study offers evidence that personalizing treatment of ER-positive breast cancers to PI3K inhibitor therapy may benefit from an analysis of PIK3CA-E545K-AKT1-estrogen signaling pathways. Cancer Res; 76(13); 3989-4001. ©2016 AACR.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Poornima
authors.initials: P
authors.lastname: Bhat-Nakshatri
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Chirayu P
authors.initials: CP
authors.lastname: Goswami
authors.affiliation: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.affiliation: Division of Cancer, Imperial College, London, United Kingdom.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: The Princess Margaret Cancer Centre, University Health Network; Ontario Institute for Cancer Research and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. VA Roudebush Medical Center, Indianapolis, Indiana. hnakshat@iupui.edu.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C506487:ESR1 protein, human; C484760:PIK3CA protein, human