Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis.
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.
Karantza-Wadsworth
Vassiliki
V
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
S
Kravchuk
Olga
O
Chen
Guanghua
G
Mathew
Robin
R
Jin
Shengkan
S
White
Eileen
E
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage / Q000502:physiology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000502:physiology; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability / Q000502:physiology; D019656:Loss of Heterozygosity / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics; D013312:Stress, Physiological / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011506:Proteins