Expression of PIK3CA mutant E545K in the mammary gland induces heterogeneous tumors but is less potent than mutant H1047R

D S Meyer,I Klebba,S Koren,M Bentires-Alj,M Müller,C Leroy,U Müller,R D Cardiff,H Brinkhaus

doi:10.1038/oncsis.2013.38

Abstract

The phosphoinositide 3-kinase (PI3K) signaling cascade is a key mediator of cellular growth, survival and metabolism and is frequently subverted in human cancer. The gene encoding for the alpha catalytic subunit of PI3K (PIK3CA) is mutated and/or amplified in ∼30% of breast cancers. Mutations in either the kinase domain (H1047R) or the helical domain (E545K) are most common and result in a constitutively active enzyme with oncogenic capacity. PIK3CAH1047R was previously demonstrated to induce tumors in transgenic mouse models; however, it was not known whether overexpression of PIK3CAE545K is sufficient to induce mammary tumors and whether tumor initiation by these two types of mutants differs. Here, we demonstrate that expression of PIK3CAE545K in the mouse mammary gland induces heterogenous mammary carcinomas but with a longer latency than PIK3CAH1047R-expressing mice. Our results suggest that the helical domain mutant PIK3CAE545K is a less potent inducer of mammary tumors due to less efficient activation of downstream Akt signaling.

Highlights

The phosphoinositide 3-kinase (PI3K) pathway is a key regulator of cell growth, proliferation, metabolism and survival and is often found to be hyperactivated in human cancer.[1,2] The most common aberrations of the PI3K pathway include mutation and/or amplification of PIK3CA,[3,4,5,6,7] the gene encoding the alpha catalytic subunit of the kinase (p110a), loss of expression of the PTEN phosphatase that reverses PI3K action, activation downstream of oncogenic receptor tyrosine kinases and mutation/amplification of Akt.[1]
PIK3CA gain-of-function mutations are found in B30% of human breast cancers[3,6,15,16,17] and most likely occur at an early stage of breast carcinoma development, as suggested by the similar mutation frequencies in PIK3CA found in pure ductal carcinoma in situ, ductal carcinoma in situ adjacent to invasive ductal carcinoma, and invasive ductal carcinoma.[18]
We and others have shown that PIK3CAH1047R induces mouse mammary carcinomas.[22,23,24,25]

Summary

INTRODUCTION

The phosphoinositide 3-kinase (PI3K) pathway is a key regulator of cell growth, proliferation, metabolism and survival and is often found to be hyperactivated in human cancer.[1,2] The most common aberrations of the PI3K pathway include mutation and/or amplification of PIK3CA,[3,4,5,6,7] the gene encoding the alpha catalytic subunit of the kinase (p110a), loss of expression of the PTEN phosphatase that reverses PI3K action, activation downstream of oncogenic receptor tyrosine kinases and mutation/amplification of Akt.[1]. PIK3CA gain-of-function mutations are found in B30% of human breast cancers[3,6,15,16,17] and most likely occur at an early stage of breast carcinoma development, as suggested by the similar mutation frequencies in PIK3CA found in pure ductal carcinoma in situ, ductal carcinoma in situ adjacent to invasive ductal carcinoma, and invasive ductal carcinoma.[18] Evaluation of the clinical outcome of genomic alterations in PIK3CA has produced contradictory results.[15,19,20] these studies showed that alterations in different exons of PIK3CA have varying impacts on tumor development and progression and, differ in prognostic value Both mutations are associated with lower grade and hormone receptor-positive tumors, but PIK3CAH1047R mutants are strongly associated with lymph-node negativity and PIK3CAE545K mutants with older age at diagnosis, indicating the different oncogenic potentials of the H1047R and E545K mutations.[19] This is further supported by the different frequencies of E545K (B6%) and H1047R (B15%) mutations in breast cancer.[17,21] In vivo transplantation assays have demonstrated PIK3CAH1047R to be more potent in inducing tumors[10] but another study found no trend,[12] and the exact impact of these mutations on breast cancer has remained controversial. We have demonstrated that PIK3CAE545K induces heterogeneous mammary tumors that express basal and luminal markers but is a less potent oncogene in vivo than PIK3CAH1047R

RESULTS AND DISCUSSION

MATERIALS AND METHODS

CONFLICT OF INTEREST