title: Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis.
abstract: Autophagy influences how cancer cells respond to nutrient deprivation and hypoxic stress, two hallmarks of the tumor microenvironment (TME). In this study, we explored the impact of autophagy on the pathophysiology of breast cancer cells using a novel hypoxia-dependent, reversible dominant-negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead unc-51-like autophagy-activating kinase (ULK1) mutant K46N increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. Indeed, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest cautions in the development of autophagy-based strategies for cancer treatment. Cancer Res; 77(3); 646-57. ©2016 AACR.
authors.affiliation: Department of Pediatrics, Milton Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dower
authors.affiliation: Department of Pediatrics, Milton Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Neema
authors.initials: N
authors.lastname: Bhat
authors.affiliation: Department of Pediatrics, Milton Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Milton Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. hwang3@hmc.psu.edu.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D040901:Proteomics; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D000071189:Autophagy-Related Protein-1 Homolog