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PMID: 17606641 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis.

Genes & development ·Vol. 21 ·No. 13 ·2007-07-01 ·Pages 1621-35

Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E

Abstract

Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.

MeSH Terms
Animals Apoptosis Regulatory Proteins Autophagy/physiology Beclin-1 Carcinoma/genetics,pathology DNA Damage/physiology Disease Progression Drug Resistance, Neoplasm/genetics Female Gene Amplification/physiology Genetic Predisposition to Disease Genomic Instability/physiology Loss of Heterozygosity/physiology Mammary Neoplasms, Animal/genetics,pathology Mice Mice, Inbred C57BL Mice, Transgenic Proteins/genetics Stress, Physiological/metabolism Tumor Cells, Cultured
Chemicals
Apoptosis Regulatory Proteins Beclin-1 Becn1 protein, mouse Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Karantza-Wadsworth Vassiliki
Division of Medical Oncology, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Patel Shyam
Kravchuk Olga
Chen Guanghua
Mathew Robin
Jin Shengkan
White Eileen
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1565707
Published
2007-07-01
Pages
1621-35
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1899472
Subset
IM
Grants
NCI NIH HHS · L30 CA116898 · United States
NCI NIH HHS · T32 CA99946 · United States
NCI NIH HHS · T32 CA099946 · United States
NCI NIH HHS · L30 CA116898-01 · United States
NCI NIH HHS · L30 CA116898-02 · United States
External Links
PubMed source DOI: 10.1101/gad.1565707 PMC Full Text View journal details
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