title: High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy.
abstract: Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway to understand underlying mechanisms. Resistance can be either intrinsic or acquired. We derived a series of subcloned MCF7 cell lines that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. Gene-expression studies revealed a signature of 67 genes that differentially respond to tamoxifen in sensitive vs. resistant subclones, which also predicts disease-free survival in tamoxifen-treated patients. High-throughput cell-based screens, in which >500 human kinases were independently ectopically expressed, identified 31 kinases that conferred drug resistance on sensitive cells. One of these, HSPB8, was also in the expression signature and, by itself, predicted poor clinical outcome in one cohort of patients. Further studies revealed that HSPB8 protected MCF7 cells from tamoxifen and blocked autophagy. Moreover, silencing HSBP8 induced autophagy and caused cell death. Tamoxifen itself induced autophagy in sensitive cells but not in resistant ones, and tamoxifen-resistant cells were sensitive to the induction of autophagy by other drugs. These results may point to an important role for autophagy in the sensitivity to tamoxifen.
authors.affiliation: The Virginia G Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Gonzalez-Malerva
authors.forename: Jaehong
authors.initials: J
authors.lastname: Park
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Zahra
authors.initials: Z
authors.lastname: Moradpour
authors.forename: Joseph
authors.initials: J
authors.lastname: Pearlberg
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sawyer
authors.forename: Hallam
authors.initials: H
authors.lastname: Stevens
authors.forename: Ed
authors.initials: E
authors.lastname: Harlow
authors.forename: Joshua
authors.initials: J
authors.lastname: LaBaer
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D018832:Molecular Chaperones; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D013629:Tamoxifen; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases