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

Jeff C Liu; Dong-Yu Wang; Sean E Egan; Eldad Zacksenhaus

doi:10.18632/oncotarget.6985

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

Oncotarget. 2016 Feb 23;7(8):9060-8. doi: 10.18632/oncotarget.6985.

Authors

Jeff C Liu¹, Dong-Yu Wang^{2

3}, Sean E Egan^{4

5}, Eldad Zacksenhaus^{1

6}

Affiliations

¹ Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
² Princess Margaret Cancer Center, Toronto, Ontario, Canada.
³ Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada.
⁴ Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

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) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic / genetics*
Class I Phosphatidylinositol 3-Kinases
ErbB Receptors / metabolism
Mammary Neoplasms, Experimental / classification
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / pathology
Mice
PTEN Phosphohydrolase / genetics*
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Phosphatidylinositol Phosphates / metabolism*

Substances

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