Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

  1. Vassiliki Karantza-Wadsworth1,2,
  2. Shyam Patel3,
  3. Olga Kravchuk3,
  4. Guanghua Chen3,
  5. Robin Mathew3,4,
  6. Shengkan Jin2,4,5, and
  7. Eileen White2,3,4,6,7
  1. 1 Division of Medical Oncology, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA;
  2. 2 The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;
  3. 3 Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA;
  4. 4 University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA;
  5. 5 Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA;
  6. 6 Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA

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.

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