TY - JOUR
T1 - IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer
AU - Zhang, Yinghui
AU - Wester, Lynn
AU - He, Jichao
AU - Geiger, Tamar
AU - Moerkens, Marja
AU - Siddappa, Ram
AU - Helmijr, Jean A.
AU - Timmermans, Mieke M.
AU - Look, Maxime P.
AU - Van Deurzen, Caroline H.M.
AU - Martens, John W.M.
AU - Pont, Chantal
AU - De Graauw, Marjo
AU - Danen, Erik H.J.
AU - Berns, Els M.J.J.
AU - Meerman, John H.N.
AU - Jansen, Maurice P.H.M.
AU - Van De Water, Bob
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040709957&partnerID=8YFLogxK
U2 - 10.1038/s41388-017-0027-9
DO - 10.1038/s41388-017-0027-9
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C2 - 29353882
AN - SCOPUS:85040709957
SN - 0950-9232
VL - 37
SP - 1869
EP - 1884
JO - Oncogene
JF - Oncogene
IS - 14
ER -
