Journal Article

IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer

Zhang, Yinghui, Danen, Erik H. J., Jansen, Maurice P. H. M., Pont, Chantal, Look, Maxime P., Wester, Lynn, Helmijr, Jean A., Geiger, Tamar, Meerman, John H. N., van Deurzen, Caroline H. M., Martens, John W. M., Timmermans, Mieke M., He, Jichao, Moerkens, Marja, de Graauw, Marjo, van de Water, Bob, Siddappa, Ram, Berns, Els M. J. J.

2018

Overview

Antiestrogen resistance in estrogen receptor positive (ER + ) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B , CDK10 , CDK5 , EIF2AK1 , and MAP2K5 , and the tamoxifen resistance inducers CHEK1 , PAK2 , RPS6KC1 , TTK , and TXK . The p21-activated kinase 2, PAK2 , is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2 , attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER + metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 631/67/1347 / 631/80/86/2368 / Antagonists / Antiestrogens / Apoptosis / Breast cancer / Cell Biology / Cyclin-dependent kinase 5 / Drug resistance / Drug therapy / Estrogen / Estrogen receptors / Estrogens / Extracellular signal-regulated kinase / Fulvestrant / Genetic aspects / Genetic screening / Growth factor receptors / Health aspects / Human Genetics / Insulin / Insulin-like growth factor 1 / Insulin-like growth factors / Internal Medicine / MAP kinase / Medicine / Medicine & Public Health / Metabolic pathways / Metastases / Oncology / p21-activated kinase / Protein kinases / Proteomics / Signal transduction / siRNA / Tamoxifen