Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer
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...
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Published in | Cancer research (Chicago, Ill.) Vol. 76; no. 13; pp. 3989 - 4001 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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01.07.2016
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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. |
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AbstractList | 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. This study identifies a unique signaling network downstream of PIK3CA-E545K mutation in estrogen receptor-positive breast cancers, representing about 20% of cases, which dictates the response to estrogen treatment and PI3K inhibitors. The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110 alpha subunit account for activation of this pathway in 20% to 40% of cases, particularly in estrogen receptor alpha (ER alpha )-positive breast cancers. AKT family of kinases, AKT1-3, are the downstream targets of PI3K and these kinases activate ER alpha . 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 ER alpha signaling, and we also assessed the utility of using the components of PI3K-AKT isoform-ER alpha 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 similar to 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. copyright 2016 AACR. 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. |
Author | Bhat-Nakshatri, Poornima Nakshatri, Harikrishna Magnani, Luca Lupien, Mathieu Goswami, Chirayu P Badve, Sunil |
Author_xml | – sequence: 1 givenname: Poornima surname: Bhat-Nakshatri fullname: Bhat-Nakshatri, Poornima organization: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana – sequence: 2 givenname: Chirayu P surname: Goswami fullname: Goswami, Chirayu P organization: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana – sequence: 3 givenname: Sunil surname: Badve fullname: Badve, Sunil organization: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana – sequence: 4 givenname: Luca surname: Magnani fullname: Magnani, Luca organization: Division of Cancer, Imperial College, London, United Kingdom – sequence: 5 givenname: Mathieu surname: Lupien fullname: Lupien, Mathieu organization: The Princess Margaret Cancer Centre, University Health Network; Ontario Institute for Cancer Research and Department of Medical Biophysics, University of Toronto, Ontario, Canada – sequence: 6 givenname: Harikrishna surname: Nakshatri fullname: Nakshatri, Harikrishna email: hnakshat@iupui.edu organization: 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 |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27197157$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1038_s41598_021_02643_y crossref_primary_10_1186_s12885_018_4654_5 crossref_primary_10_1016_j_jss_2017_01_018 crossref_primary_10_1016_j_semcdb_2016_08_024 crossref_primary_10_3389_fendo_2018_00219 crossref_primary_10_3389_fphar_2020_00717 crossref_primary_10_1016_j_ejmech_2018_08_010 crossref_primary_10_3390_cancers13030369 crossref_primary_10_1016_j_bbcan_2017_03_008 crossref_primary_10_1007_s12253_018_0522_5 crossref_primary_10_1007_s10549_019_05401_x crossref_primary_10_1186_s13058_018_0963_5 crossref_primary_10_1038_s41598_018_27044_6 crossref_primary_10_1016_j_bbrc_2017_05_177 crossref_primary_10_1016_j_bcp_2021_114659 |
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Snippet | The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110α subunit account for... Abstract The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110α subunit... This study identifies a unique signaling network downstream of PIK3CA-E545K mutation in estrogen receptor-positive breast cancers, representing about 20% of... |
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SubjectTerms | Biomarkers, Tumor - genetics Breast Neoplasms - genetics Breast Neoplasms - pathology Class I Phosphatidylinositol 3-Kinases Estrogen Receptor alpha - genetics Female Gene Expression Profiling Gene Regulatory Networks Humans Mutation - genetics Phosphatidylinositol 3-Kinases - genetics Proto-Oncogene Proteins c-akt - genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal Transduction Tumor Cells, Cultured |
Title | Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer |
URI | https://www.ncbi.nlm.nih.gov/pubmed/27197157 https://search.proquest.com/docview/1801434775 https://search.proquest.com/docview/1811909941 |
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