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

被引：33

作者：

Zhang, Yinghui ^{[1
]}

Wester, Lynn ^{[1
]}

He, Jichao ^{[1
]}

Geiger, Tamar ^{[2
]}

Moerkens, Marja ^{[1
]}

Siddappa, Ram ^{[1
]}

Helmijr, Jean A. ^{[3
]}

Timmermans, Mieke M. ^{[3
]}

Look, Maxime P. ^{[3
]}

van Deurzen, Caroline H. M. ^{[3
,4
]}

Martens, John W. M. ^{[3
]}

Pont, Chantal ^{[1
]}

de Graauw, Marjo ^{[1
]}

Danen, Erik H. J. ^{[1
]}

Berns, Els M. J. J. ^{[3
]}

Meerman, John H. N. ^{[1
]}

Jansen, Maurice P. H. M. ^{[3
]}

van de Water, Bob ^{[1
]}

机构：

[1] Leiden Univ, Leiden Acad Ctr Drug Res, Div Toxicol, Leiden, Netherlands

[2] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Fac Med, Tel Aviv, Israel

[3] Dept Med Oncol & Canc Genom Netherlands, Rotterdam, Netherlands

[4] Erasmus Univ, Erasmus MC Canc Inst, Dept Pathol, Med Ctr, Rotterdam, Netherlands

来源：

ONCOGENE | 2018年 / 37卷 / 14期

关键词：

TAMOXIFEN RESISTANCE; P21-ACTIVATED-KINASE-1; PAK1; ENDOCRINE RESISTANCE; CELL-PROLIFERATION; NEURITE OUTGROWTH; GROWTH-FACTORS; BETA-CATENIN; I RECEPTOR; EXPRESSION; PATHWAY;

D O I：

10.1038/s41388-017-0027-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 PIX alpha/beta as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIX alpha/beta modulate IGF1R signaling-driven cell scattering. Targeting PIX alpha/beta 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.

引用

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页码：1869 / 1884

页数：16

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