High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy

Laura Gonzalez-Malerva, Jaehong Park, Lihua Zou, Yanhui Hu, Zahra Moradpour, Joseph Pearlberg, Jacqueline Sawyer, Hallam Stevens, Ed Harlow*, Joshua LaBaer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2058-2063
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number5
DOIs
StatePublished - Feb 1 2011

Keywords

  • Estrogen receptor
  • Functional screen

ASJC Scopus subject areas

  • General

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