Artemin, a member of the glial cell line-derived neurotrophic factor family of ligands, is HER2-regulated and mediates acquired trastuzumab resistance by promoting cancer stem cell-like behavior in mammary carcinoma cells.

Abstract

Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells.

• Authors: Keshuo Ding, Arindam Banerjee, Sheng Tan, JunSong Zhao, Qian Zhuang, Rui Li, Pengxu Qian, Suling Liu, Zheng-Sheng Wu, Peter E Lobie, Tao Zhu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 23 Pg. 16057-71 (Jun 06 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24737320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ARTN protein, human
• Antibodies, Monoclonal, Humanized
• DNA Primers
• Glial Cell Line-Derived Neurotrophic Factor
• Nerve Tissue Proteins
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Base Sequence
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• DNA Primers
• Drug Resistance, Neoplasm
• Female
• Glial Cell Line-Derived Neurotrophic Factor (physiology)
• Humans
• Neoplastic Stem Cells (drug effects, pathology)
• Nerve Tissue Proteins (antagonists & inhibitors, physiology)
• Polymerase Chain Reaction
• Receptor, ErbB-2 (physiology)
• Trastuzumab