Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

M R Sheen,S Fiering,M J Allegrezza,M Rutkowski,J R Conejo-Garcia,J D Marotti

doi:10.1038/oncsis.2016.65

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/fl deletion and KrasG12D also 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;KrasG12D with 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.

Highlights

Receptor tyrosine kinase-phosphatidylinositol 3-kinase (PI3K)signaling is a central integrator of metabolism, cell growth and cell survival, and deregulated PI3K signaling increases tumorigenicity.[1,2] Cancer-associated mutations occur in several components of the pathway including activating mutations of both the PI3K catalytic subunit α-isoform gene (PIK3CA, p110α)[3] and the downstream signaling molecule AKT1,4 as well as deletion of the negative pathway regulator, PTEN.[5]
Mammary tumors from p53fl/fl;KrasG12D;myr-p110αwt/fl and p53fl/fl; KrasG12D;myr-p110αfl/fl had significantly increased levels of total p110α (1.3-fold) and phosphorylated form of AKT (p-AKT) levels (1.3-fold), as compared with p53fl/fl;myr-p110αwt/fl and p53fl/fl;myr-p110αfl/fl mammary tumors as shown in Figures 3c and d. These findings show that PI3K signaling can be further activated by cooperation of myr-p110α with KrasG12D mutation, and the rate of tumor initiation is strongly influenced by the level of PI3K activity
These findings show that increased PI3K activity mediated by two copies of myr-p110α, when combined with either p53fl/fl or p53fl/fl;KrasG12D, have the potential to skew mammary tumors from a sarcomatoid phenotype to a carcinoma phenotype more common in humans

Summary

Introduction

Receptor tyrosine kinase-phosphatidylinositol 3-kinase (PI3K)signaling is a central integrator of metabolism, cell growth and cell survival, and deregulated PI3K signaling increases tumorigenicity.[1,2] Cancer-associated mutations occur in several components of the pathway including activating mutations of both the PI3K catalytic subunit α-isoform gene (PIK3CA, p110α)[3] and the downstream signaling molecule AKT1,4 as well as deletion of the negative pathway regulator, PTEN.[5]. The significance of p110α in cancer is demonstrated by the high frequency of activating mutations in many common human cancers that increase the catalytic activity of PI3K.3,6. High-throughput RNA sequencing and tumor resequencing have revealed that hyperactivating mutations in the PI3K signaling pathway occur in a substantial percentage of breast cancers.[7] The PIK3CA gene itself, encoding the p110α catalytic subunit, is the most frequently mutated gene in breast cancer,[8,9] with mutations in 25–40% of all breast cancers.[10,11] the prognostic implications of p110α mutations remain unclear. The association of PI3K mutations with poor prognosis has been reported,[12,13] others have described a correlation with improved outcome.[14,15]

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