IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer
- Zhang, Y.
- Wester, L.
- He, J.
- Geiger, T.
- Moerkens, M.
- Siddappa, R.
- Helmijr, J.A.
- Timmermans, M.M.
- Look, M.P.
- Deurzen, C.H.M. van
- Martens, J.W.M.
- Pont, C.M.
- Graauw, M. de
- Danen, E.H.J.
- Berns, E.M.J.J.
- Jansen, M.P.H.M.
- Meerman, J.H.N.
- Water, B. van de
DOIAbstract
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 ...
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