| Literature DB >> 29353882 |
Yinghui Zhang1, Lynn Wester2, Jichao He2, Tamar Geiger3, Marja Moerkens2, Ram Siddappa2, Jean A Helmijr4, Mieke M Timmermans4, Maxime P Look4, Caroline H M van Deurzen4,5, John W M Martens4, Chantal Pont2, Marjo de Graauw2, Erik H J Danen2, Els M J J Berns4, John H N Meerman2, Maurice P H M Jansen4, Bob van de Water6.
Abstract
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.Entities:
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Year: 2018 PMID： 29353882 DOI： 10.1038/s41388-017-0027-9
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867