Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL.

Abstract

Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR.

• Authors: Ting-Yu Chang, Hsin-An Chen, Ching-Feng Chiu, Yi-Wen Chang, Tsang-Chih Kuo, Po-Chun Tseng, Weu Wang, Mien-Chie Hung, Jen-Liang Su
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 13 Pg. 3916-28 (07 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27216190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Adenovirus E1A Proteins
• Antineoplastic Agents, Phytogenic
• Biomarkers, Tumor
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• MIRN494 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins
• Receptor Protein-Tyrosine Kinases
• Mitogen-Activated Protein Kinase 14
• DICER1 protein, human
• Ribonuclease III
• DEAD-box RNA Helicases
• Paclitaxel
• Axl Receptor Tyrosine Kinase

Topics

• Adenoviridae (genetics)
• Adenovirus E1A Proteins (metabolism)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CCAAT-Enhancer-Binding Proteins (metabolism)
• DEAD-box RNA Helicases (metabolism)
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics)
• Mitogen-Activated Protein Kinase 14 (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins (metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Ribonuclease III (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Axl Receptor Tyrosine Kinase