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

Autor: Lynn Wester, Marjo de Graauw, Tamar Geiger, John W.M. Martens, Yinghui Zhang, Chantal Pont, Bob van de Water, Jean A. Helmijr, Maurice P.H.M. Jansen, Maxime P. Look, Marja Moerkens, Caroline H M van Deurzen, John H. N. Meerman, Els M.J.J. Berns, Erik H.J. Danen, Mieke M. Timmermans, Ram Siddappa, Jichao He
Přispěvatelé: Pathology, Medical Oncology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
MAPK/ERK pathway
Cancer Research
Antineoplastic Agents
Hormonal
Estrogen receptor
Breast Neoplasms
Biology
Gene Expression Regulation
Enzymologic
Receptor
IGF Type 1
03 medical and health sciences
0302 clinical medicine
SDG 3 - Good Health and Well-being
Cell Line
Tumor
Genetics
medicine
Humans
Gene silencing
RNA
Small Interfering
skin and connective tissue diseases
Molecular Biology
PI3K/AKT/mTOR pathway
Insulin-like growth factor 1 receptor
Fulvestrant
Estrogen Antagonists
Receptors
Somatomedin
Antiestrogen
High-Throughput Screening Assays
Gene Expression Regulation
Neoplastic
body regions
Tamoxifen
HEK293 Cells
030104 developmental biology
p21-Activated Kinases
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
MCF-7 Cells
Cancer research
Female
Rho Guanine Nucleotide Exchange Factors
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
medicine.drug
Zdroj: Oncogene, 37(14), 1869-1884. Nature Publishing Group
ISSN: 0950-9232
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: