PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α Academic Article uri icon

Overview

MeSH Major

  • Extracellular Signal-Regulated MAP Kinases
  • Indazoles
  • Melanoma
  • Neurofibromin 1
  • Phenformin
  • Piperazines

abstract

  • Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85α is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of Pik3r1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85α increases the amount of p110α-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110α-selective pharmacological inhibition effectively blocks transformation driven by partial p85α loss both in vitro and in vivo. Together, our data suggest that p85α plays a tumor-suppressive role in transformation, and suggest that p110α-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss.

publication date

  • July 3, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5502636

Digital Object Identifier (DOI)

  • 10.1073/pnas.1704706114

PubMed ID

  • 28630349

Additional Document Info

start page

  • 7095

end page

  • 7100

volume

  • 114

number

  • 27