title: Artemin stimulates radio- and chemo-resistance by promoting TWIST1-BCL-2-dependent cancer stem cell-like behavior in mammary carcinoma cells.
abstract: Artemin (ARTN) has been reported to promote a TWIST1-dependent epithelial to mesenchymal transition of estrogen receptor negative mammary carcinoma (ER-MC) cells associated with metastasis and poor survival outcome. We therefore examined a potential role of ARTN in the promotion of the cancer stem cell (CSC)-like phenotype in mammary carcinoma cells. Acquired resistance of ER-MC cells to either ionizing radiation (IR) or paclitaxel was accompanied by increased ARTN expression. Small interfering RNA (siRNA)-mediated depletion of ARTN in either IR- or paclitaxel-resistant ER-MC cells restored cell sensitivity to IR or paclitaxel. Expression of ARTN was enriched in ER-MC cells grown in mammospheric compared with monolayer culture and was also enriched along with BMI1, TWIST1, and DVL1 in mammospheric and ALDH1+ populations. ARTN promoted mammospheric growth and self-renewal of ER-MC cells and increased the ALDH1+ population, whereas siRNA-mediated depletion of ARTN diminished these CSC-like cell behaviors. Furthermore, increased ARTN expression was significantly correlated with ALDH1 expression in a cohort of ER-MC patients. Forced expression of ARTN also dramatically enhanced tumor initiating capacity of ER-MC cells in xenograft models at low inoculum. ARTN promotion of the CSC-like cell phenotype was mediated by TWIST1 regulation of BCL-2 expression. ARTN also enhanced mammosphere formation and the ALDH1+ population in estrogen receptor-positive mammary carcinoma (ER+MC) cells. Increased expression of ARTN and the functional consequences thereof may be one common adaptive mechanism used by mammary carcinoma cells to promote cell survival and renewal in hostile tumor microenvironments.
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1023, New Zealand.
authors.forename: Arindam
authors.initials: A
authors.lastname: Banerjee
authors.forename: PengXu
authors.initials: P
authors.lastname: Qian
authors.forename: Zheng-Sheng
authors.initials: ZS
authors.lastname: Wu
authors.forename: Xiaoge
authors.initials: X
authors.lastname: Ren
authors.forename: Michael
authors.initials: M
authors.lastname: Steiner
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Bougen
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.forename: Dong-Xu
authors.initials: DX
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011960:Receptors, Estrogen / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C490886:ARTN protein, human; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D017239:Paclitaxel