Elevated PI3K signaling drives multiple Breast Cancer subtypes

Jessica R Adams,Eldad Zacksenhaus,Jeff C Liu,Sean E Egan,Nathan F Schachter

doi:10.18632/oncotarget.285

Abstract

Most human breast tumors have mutations that elevate signaling through a key metabolic pathway that is induced by insulin and a number of growth factors. This pathway serves to activate an enzyme known as phosphatidylinositol 3' kinase (PI3K) as well as to regulate proteins that signal in response to lipid products of PI3K. The specific mutations that activate this pathway in breast cancer can occur in genes coding for tyrosine kinase receptors, adaptor proteins linked to PI3K, catalytic and regulatory subunits of PI3K, serine/threonine kinases that function downstream of PI3K, and also phosphatidylinositol 3' phosphatase tumor suppressors that function to antagonize this pathway. While each genetic change results in net elevation of PI3K pathway signaling, and all major breast cancer subtypes show pathway activation, the specific mutation(s) involved in any one tumor may play an important role in defining tumor subtype, prognosis and even sensitivity to therapy. Here, we describe mouse models of breast cancer with elevated PI3K signaling, and how they may be used to guide development of novel therapeutics.

Highlights

In 1988, the phosphatidylinositol kinase that copurified with tyrosine kinase receptors was found to phosphorylate phosphatidylinositol lipids at the 3’ hydroxyl position [1, 2]
In MCF10A cells expressing high levels of HER2/Neu, a kinase domain mutant of PIK3CA (H1047R) induced expression of Heregulin, the ligand that activates HER2/HER3 signaling through the phosphatidylinositol 3’ kinase (PI3K) pathway [113]
Mouse models of breast cancer have been refined through use of gene targeting to generate conditional mutants and transgenics that mimic pathological features of specific breast cancer subtypes [114,115,116,117,118]

Summary

INTRODUCTION

In 1988, the phosphatidylinositol kinase that copurified with tyrosine kinase receptors was found to phosphorylate phosphatidylinositol lipids at the 3’ hydroxyl position [1, 2]. PI3K signaling is stimulated in response to activation of many growth factor receptors, most potently by the insulin receptor tyrosine kinase (InsR). PIP3 subsequently recruits, and in some cases activates, a series of signaling proteins, most of which contain PIP3binding pleckstrin homology (PH) domains. Best studied among these PIP3 targets are the Akt (1, 2 3)/PKB (α, β or γ) AGC-family serine/threonine kinases [9,10,11], as well as PDK1 which phosphorylates Akt at threonine 308. Phosphorylation of PRAS40 by Akt induces sequestration of p-PRAS40 by 14-3-3 proteins, which prevents it from inhibiting the mTOR, Raptor, mLST8 and Deptor-containing TORC1 serine/threonine kinase complex [12,13,14]. Both constitutive and inducible negative regulators act to antagonize the PI3K pathway, maintaining the c-MET

Transcription of Growth factor receptor genes AAAAA

MOUSE MODELS

Findings

USING THE MOUSE TO GUIDE EFFECTIVE THERAPY