Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3030-5. doi: 10.1073/pnas.1523693113. Epub 2016 Feb 29.

Abstract

Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

Keywords: RNAi; breast cancer; mouse models; targeted therapies; tumor suppressors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genes, erbB-2
  • Humans
  • MAP Kinase Kinase 1 / physiology
  • MAP Kinase Signaling System / physiology*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / physiopathology*
  • Mammary Tumor Virus, Mouse / physiology
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / physiology*
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / physiology*
  • Signal Transduction / physiology

Substances

  • Neoplasm Proteins
  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • PTEN Phosphohydrolase
  • Pten protein, mouse