PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model

Oncogene. 2016 Jun 23;35(25):3314-23. doi: 10.1038/onc.2015.393. Epub 2015 Oct 12.

Abstract

Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / genetics
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism*
  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Disease Models, Animal*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Burden*

Substances

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases