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

Beclin 1 regulates growth factor receptor signaling in breast cancer.

Author information

1
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
2
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
3
Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, USA.

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.

PMID:
25639875
PMCID:
PMC4522409
DOI:
10.1038/onc.2014.454
[Indexed for MEDLINE]
Free PMC Article

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