title: Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.
abstract: The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53fl/fldeletion and KrasG12Dalso regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110α accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53fl/fl;KrasG12Dwith no or one copy of myr-p110α had predominantly sarcomatoid features, whereas two copies of myr-p110α resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110α in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors: M R
authors: MR
authors: Sheen
authors: Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.|Geisel School of Medicine at Dartmouth, Hanover, NH, USA.|Norris Cotton Cancer Center, Lebanon, NH, USA.
authors: J D
authors: JD
authors: Marotti
authors: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors: M J
authors: MJ
authors: Allegrezza
authors: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors: M
authors: M
authors: Rutkowski
authors: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors: J R
authors: JR
authors: Conejo-Garcia
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.|Norris Cotton Cancer Center, Lebanon, NH, USA.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors: S
authors: S
authors: Fiering