Beclin 1 regulates growth factor receptor signaling in breast cancer

Oncogene. 2015 Oct 16;34(42):5352-62. doi: 10.1038/onc.2014.454. Epub 2015 Feb 2.

Abstract

Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P(-)) endosomes to PI3P(+) endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P(-)/APPL(+)-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Apoptosis Regulatory Proteins / physiology*
  • Autophagy-Related Protein 5
  • Beclin-1
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Class III Phosphatidylinositol 3-Kinases / physiology
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • MCF-7 Cells
  • Membrane Proteins / physiology*
  • Microtubule-Associated Proteins / physiology
  • Nuclear Proteins
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Growth Factor / physiology*
  • Signal Transduction / physiology*
  • Transcription Factors

Substances

  • APPL1 protein, human
  • ATG5 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 5
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • PI3KCA protein, human
  • Receptors, Growth Factor
  • Transcription Factors
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Class III Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases