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

Oncogene volume 37, pages 1869–1884 (2018)Cite this article

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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.

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Fig. 1: Identification of determinants in IGF1R-mediated tamoxifen resistance by kinome siRNA Screen.
Fig. 2: Clinical relevance of 10 IGF1R-mediated tamoxifen resistance hits
Fig. 3: Targeting effects on antiestrogen dose-responses of the IGF1R-mediated tamoxifen resistance hits with clinical relevance.
Fig. 4: Targeting of tamoxifen resistance inducer PAK2 abrogates IGF1R-mediated antiestrogen resistance.
Fig. 5: PAK signaling in response to IGF-1 stimulation and interaction with IGF-1 signaling network.
Fig. 6: PAK2 is activated apart from PI3K/AKT and MAPK/ERK pathways and promotes cell-cycle progression and anti-apoptosis in IGF1R-mediated antiestrogen resistance.
Fig. 7: Involvement of PAK2 survival signaling components PIXα/β in IGF1R-mediated antiestrogen resistance.
Fig. 8: Relevance of PAK2 expression in primary tumor specimens to poor outcome of metastatic breast cancer patients after first-line tamoxifen.

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Acknowledgements

This study was supported by the research project of Top Institute Pharma (Leiden, The Netherlands) “Nuclear Receptors in Targeted Cancer Therapy” (T3-107) and the research project of Dutch Cancer Society “Novel Protein Kinase Targets in Receptor Tyrosine Kinase-mediated Drug Resistant Breast Cancer” (UL-2011-5124).

Author contributions

YZ, JHNM, MPHMJ, and BvdW designed research. RS, YZ, and EHJD designed automated high-throughput screening. YZ performed screening and analyzed screening data. TG, CP, YZ, and MdG contributed to SILAC phospho-proteomics and data analysis. JAH, MMT, MPL, CHMvD, JWMM, EMJJB, and MPHMJ contributed to clinical evaluations and analyses. YZ, LW, JH, and MM carried out experimental assays. YZ, MPHMJ, and BvdW wrote the manuscript.

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  1. Yinghui Zhang and Lynn Wester are contributed equally to this work

Authors and Affiliations

  1. Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

    Yinghui Zhang, Lynn Wester, Jichao He, Marja Moerkens, Ram Siddappa, Chantal Pont, Marjo de Graauw, Erik H. J. Danen, John H. N. Meerman & Bob van de Water

  2. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Tamar Geiger

  3. Department of Medical Oncology and Cancer Genomic Netherlands, Rotterdam, The Netherlands

    Jean A. Helmijr, Mieke M. Timmermans, Maxime P. Look, Caroline H. M. van Deurzen, John W. M. Martens, Els M. J. J. Berns & Maurice P. H. M. Jansen

  4. Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    Caroline H. M. van Deurzen

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Zhang, Y., Wester, L., He, J. et al. IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer. Oncogene 37, 1869–1884 (2018). https://doi.org/10.1038/s41388-017-0027-9

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