title: 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.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Keshuo
authors.initials: K
authors.lastname: Ding
authors.affiliation: the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, and.
authors.forename: Arindam
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tan
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: JunSong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Pengxu
authors.initials: P
authors.lastname: Qian
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China, the Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, People's Republic of China, the Department of Pathology, Shanghai Medical College, Fudan University, Yangpu, Shanghai, China.
authors.forename: Zheng-Sheng
authors.initials: ZS
authors.lastname: Wu
authors.affiliation: the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, and the National Cancer Institute of Singapore, National University Health System, Singapore 119074 csipel@nus.edu.sg.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.affiliation: From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China, zhut@ustc.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016133:Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D017931:DNA Primers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C490886:ARTN protein, human; C508053:ERBB2 protein, human
keywords: Breast Cancer; Cancer Stem Cells; Chemoresistance; Oncogene; Tumor Metastases
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