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PMID: 26814435 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Common and distinct features of mammary tumors driven by Pten-deletion or activating Pik3ca mutation.

Oncotarget ·Vol. 7 ·No. 8 ·2016-02-23 ·Pages 9060-8

Liu JC, Wang DY, Egan SE, Zacksenhaus E

Abstract

PTEN loss and PIK3CA activation both promote the accumulation of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3). While these proteins also have distinct biochemical functions, beyond the regulation of PIP3, little is known about the consequences of these differences in vivo. Here, we directly compared cancer signalling in mammary tumors from MMTV-Cre:Ptenf/f and MMTV-Cre:Pik3ca(LSL-H1047R) mice. Using unsupervised hierarchical clustering we found that whereas MMTV-Cre:Pik3ca(LSL-H1047R)-derived tumors fall into two separate groups, designated squamous-likeEx and class14(Ex), MMTV-Cre:Ptenf/f tumors cluster as one group together with PIK3CA(H1047R) class14(Ex), exhibiting a 'luminal' expression profile. Gene Set Enrichment Analysis (GSEA) of Pten(Δ)ˆ† and PIK3CA(H1047R) class14(Ex) tumors revealed very similar profiles of signalling pathways as well as some interesting differences. Analysis of 18 signalling signatures revealed that PI3K signalling is significantly induced whereas EGFR signalling is significantly reduced in Pten(∆) versus PIK3CA(H1047R) tumors. Thus, Pten(∆) and PIK3CA(H1047R) tumors exhibit discernable differences that may impact tumorigenesis and response to therapy.

Keywords
PIK3CA PTEN bioinformatics breast cancer mouse models
MeSH Terms
Animals Cell Transformation, Neoplastic/genetics Class I Phosphatidylinositol 3-Kinases ErbB Receptors/metabolism Mammary Neoplasms, Experimental/classification,genetics,pathology Mice PTEN Phosphohydrolase/genetics Phosphatidylinositol 3-Kinases/genetics,metabolism Phosphatidylinositol Phosphates/metabolism
Chemicals
Phosphatidylinositol Phosphates phosphatidylinositol 3,4,5-triphosphate Class I Phosphatidylinositol 3-Kinases Pik3ca protein, mouse EGFR protein, mouse ErbB Receptors PTEN Phosphohydrolase Pten protein, mouse
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Liu Jeff C
Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
Wang Dong-Yu
Princess Margaret Cancer Center, Toronto, Ontario, Canada. | Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada.
Egan Sean E
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. | Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Zacksenhaus Eldad
Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada. | Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
References (24)
24 references, click to expand
  1. Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
    Cell. 2011 Jan 21;144(2):187-99 PMID: 21241890
  2. Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer.
    Proc Natl Acad Sci U S A. 2012 Apr 10;109 (15):5832-7 PMID: 22460789
  3. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  4. The functions and regulation of the PTEN tumour suppressor.
    Nat Rev Mol Cell Biol. 2012 Apr 04;13(5):283-96 PMID: 22473468
  5. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.
    Mol Cell Proteomics. 2015 Jul;14(7):1959-76 PMID: 25953087
  6. Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation.
    Cancer Res. 2011 Apr 1;71(7):2706-17 PMID: 21324922
  7. A pathway-based classification of human breast cancer.
    Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6994-9 PMID: 20335537
  8. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways.
    Nat Med. 2011 Apr;17(4):461-9 PMID: 21399647
  9. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.
    Oncotarget. 2014 Jul 15;5(13):4603-50 PMID: 25051360
  10. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation.
    PLoS One. 2010 Nov 15;5(11):e13984 PMID: 21085593
  11. A Tumor initiating cell-enriched prognostic signature for HER2+:ERα- breast cancer; rationale, new features, controversies and future directions.
    Oncotarget. 2013 Aug;4(8):1317-28 PMID: 23945331
  12. Cancer: Precise control of localized signals.
    Nature. 2015 Jun 4;522(7554):38-40 PMID: 26017306
  13. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
    Cell. 2015 Oct 8;163(2):506-19 PMID: 26451490
  14. PTEN is a protein tyrosine phosphatase for IRS1.
    Nat Struct Mol Biol. 2014 Jun;21(6):522-7 PMID: 24814346
  15. Elevated PI3K signaling drives multiple breast cancer subtypes.
    Oncotarget. 2011 Jun;2(6):435-47 PMID: 21646685
  16. Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway.
    Oncotarget. 2014 May 30;5(10):3029-38 PMID: 24912489
  17. Comprehensive molecular portraits of human breast tumours.
    Nature. 2012 Oct 4;490(7418):61-70 PMID: 23000897
  18. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.
    Nat Rev Cancer. 2006 Mar;6(3):184-92 PMID: 16453012
  19. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs.
    Oncogene. 2011 Jul 21;30(29):3222-33 PMID: 21358673
  20. A secreted PTEN phosphatase that enters cells to alter signaling and survival.
    Science. 2013 Jul 26;341(6144):399-402 PMID: 23744781
  21. Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts.
    Genome Biol. 2013 Nov 12;14(11):R125 PMID: 24220145
  22. PI3K pathway alterations in cancer: variations on a theme.
    Oncogene. 2008 Sep 18;27(41):5497-510 PMID: 18794884
  23. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.
    Science. 2013 Jul 26;341(6144):395-9 PMID: 23888040
  24. Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.
    EMBO Mol Med. 2014 Oct 20;6(12 ):1542-60 PMID: 25330770
Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.6985
Published
2016-02-23
Pages
9060-8
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4891026
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.6985 PMC Full Text View journal details
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