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

• DOI: 10.1073/pnas.1018157108
• Publication Date: 2011-01-14T02:02:13Z
• Authors: Laura Gonzalez-Ma...; Jaehong Park; Lihua Zou; Yanhui Hu; Zahra Moradpour; Joseph Pearlberg; Jacqueline Sawyer; Hallam Stevens; Ed Harlow; Joshua LaBaer
• Keywords: Ectopic expression

Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway understand underlying mechanisms. can be either intrinsic or acquired. We derived series of subcloned MCF7 cell lines that were highly sensitive naturally resistant studied the factors lead drug resistance. Gene-expression studies revealed signature 67 genes differentially respond vs. subclones, which also predicts disease-free survival tamoxifen-treated patients. High-throughput cell-based screens, >500 human kinases independently ectopically expressed, identified 31 conferred resistance on cells. One these, HSPB8, was expression and, by itself, predicted poor clinical outcome one cohort Further HSPB8 protected cells from blocked autophagy. Moreover, silencing HSBP8 induced autophagy caused death. Tamoxifen itself but not ones, tamoxifen-resistant induction other drugs. These results may point an important role for sensitivity tamoxifen.