Autophagy, Cell Viability, and Chemoresistance Are Regulated By miR-489 in Breast Cancer

Mol Cancer Res. 2018 Sep;16(9):1348-1360. doi: 10.1158/1541-7786.MCR-17-0634. Epub 2018 May 21.


It is postulated that the complexity and heterogeneity in cancer may hinder most efforts that target a single pathway. Thus, discovery of novel therapeutic agents targeting multiple pathways, such as miRNAs, holds promise for future cancer therapy. One such miRNA, miR-489, is downregulated in a majority of breast cancer cells and several drug-resistant breast cancer cell lines, but its role and underlying mechanism for tumor suppression and drug resistance needs further investigation. The current study identifies autophagy as a novel pathway targeted by miR-489 and reports Unc-51 like autophagy activating kinase 1 (ULK1) and lysosomal protein transmembrane 4 beta (LAPTM4B) to be direct targets of miR-489. Furthermore, the data demonstrate autophagy inhibition and LAPTM4B downregulation as a major mechanism responsible for miR-489-mediated doxorubicin sensitization. Finally, miR-489 and LAPTM4B levels were inversely correlated in human tumor clinical specimens, and more importantly, miR-489 expression levels predict overall survival in patients with 8q22 amplification (the region in which LAPTM4B resides).Implications: These findings expand the understanding of miR-489-mediated tumor suppression and chemosensitization in and suggest a strategy for using miR-489 as a therapeutic sensitizer in a defined subgroup of resistant breast cancer patients. Mol Cancer Res; 16(9); 1348-60. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • Female
  • Genetic Therapy / methods
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • MicroRNAs / administration & dosage*
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microarray Analysis
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Random Allocation
  • Transfection
  • Xenograft Model Antitumor Assays


  • Intracellular Signaling Peptides and Proteins
  • LAPTM4B protein, human
  • MIRN489 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Oncogene Proteins
  • Doxorubicin
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human