title: Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway.
abstract: HER2-positive breast cancer initially responds to trastuzumab treatment, but over time, resistance develops and rapid cancer progression occurs, for which various explanations have been proposed. Here we tested the hypothesis that induction of the unfolded protein response (UPR) could override HER2 inhibition by trastuzumab, leading to the re-activation of growth signaling and the activation of the downstream target Lipocalin 2 (LCN2). Trastuzumab significantly inhibited the basal expression of LCN2 in HER2 (+) SKBr3 human breast cancer cells. The induction of the UPR completely abrogated trastuzumab-mediated LCN2 downregulation, and, in fact caused an increase in transcription and secretion of LCN2 over baseline. Reduction of the UPR using 4-phenyl butyric acid (PBA) a chemical chaperone that ameliorates ER stress, restored trastuzumab-mediated inhibition. Inhibition of the PI3K/AKT signaling pathway in trastuzumab-treated/UPR-induced SKBr3 cells partially reduced the upregulation of LCN2. These results suggest that the UPR is a possible way to override the effect of trastuzumab in HER2(+) cancer cells.
authors.affiliation: The Laboratory of Immunology, Department of Medicine, Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0815, United States.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kumandan
authors.forename: Navin R
authors.initials: NR
authors.lastname: Mahadevan
authors.forename: Kevin
authors.initials: K
authors.lastname: Chiu
authors.forename: Alexandra
authors.initials: A
authors.lastname: DeLaney
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D000068878:Trastuzumab; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000209:Acute-Phase Proteins; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D007093:Imidazoles; D000071068:Lipocalin-2; D054834:Lipocalins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D000068878:Trastuzumab; C497249:DDIT3 protein, human; C489506:LCN2 protein, human; C508053:ERBB2 protein, human; C531198:dactolisib