Abstract 4349: Genome-wide kinase and phosphatase siRNA screen identifies clinically relevant targets in IGF1R signaling-mediated antiestrogen resistance in breast cancer.

Abstract

Abstract Antiestrogen resistance of breast cancer has been linked to increased growth factor receptor signaling such as invoked by the insulin-like growth factor 1 (IGF-1) receptor (IGF1R). We have previously shown that increased IGF1R signaling by ectopic IGF1R overexpression in MCF7 cells (MCF7-IGF1R) directly drives an estrogen receptor (ER)-independent cell proliferation in MCF7 cells that leads to antiestrogen resistance. To identify components of the downstream IGF1R signaling pathways that mediate antiestrogen resistance, we have performed a human genome-wide kinase and phosphatase siRNA screen under tamoxifen resistance condition (1 μM 4-OH-tamoxifen, 1 nM estradiol, and 100 ng/ml IGF-1) in MCF7-IGF1R cells. We identified 174 kinases and phosphatases that increased or decreased tamoxifen resistance. Of these, 14 significantly correlated with the time to disease progression of metastatic breast cancer patients treated with first-line tamoxifen monotherapy, including ADRA1B, BMPR1B, CDK10, CDK5, EIF2AK1 and MAP2K5. Low expression of these six genes in patients correlated with short time to disease progression and silencing of these genes in MCF7-IGF1R cells further increased proliferation under tamoxifen resistance condition. Low expression of the other eight genes in patients correlated with longer time the time to disease progression and silencing of these genes in MCF7-IGF1R cells decreased proliferation under tamoxifen resistance condition Therefore, these latter genes may represent novel drug targets that may be useful to restore tamoxifen sensitivity in breast cancer. Knockdown of two of these genes suppressed IGF1R-mediated effects and restored the anti-proliferative effect of tamoxifen in a dose dependent manner, suggesting synthetic lethality between the knockdowns and tamoxifen. Further study of one of these genes revealed that stable knockdown inhibits proliferation and three-dimensional growth under tamoxifen resistance condition, accompanied with an increase in G1/G0 arrest and mild induction of apoptosis. These effects are independent of PI3K/AKT and MAPK/ERK signaling pathways, and suggest that an as yet unknown pathway plays a decisive role in tamoxifen resistance induced by IGF1R signaling. Citation Format: John H. Meerman, Yinghui Zhang, Maurice P. Jansen, Ramakrishnaiah Siddapa, Sreenivasa Ramaiahgari, Leo Price, Erik Danen, Els M. Berns, John Foekens, Bob van de Water. Genome-wide kinase and phosphatase siRNA screen identifies clinically relevant targets in IGF1R signaling-mediated antiestrogen resistance in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4349. doi:10.1158/1538-7445.AM2013-4349