Modeling the estrogen receptor to growth factor receptor signaling switch in human breast cancer cells |
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| Authors: | Chun Chen William T. Baumann Robert Clarke John J. Tyson |
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| Affiliation: | 1. Department of Biological Sciences, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA;2. Department of Electrical & Computer Engineering, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA;3. Graduate Program in Genetics, Bioinformatics and Computational Biology, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA;4. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC 20057, USA |
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| Abstract: | Breast cancer cells develop resistance to endocrine therapies by shifting between estrogen receptor (ER)-regulated and growth factor receptor (GFR)-regulated survival signaling pathways. To study this switch, we propose a mathematical model of crosstalk between these pathways. The model explains why MCF7 sub-clones transfected with HER2 or EGFR show three GFR-distribution patterns, and why the bimodal distribution pattern can be reversibly modulated by estrogen. The model illustrates how transient overexpression of ER activates GFR signaling and promotes estrogen-independent growth. Understanding this survival-signaling switch can help in the design of future therapies to overcome resistance in breast cancer. |
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| Keywords: | AKT, a serine/threonine-specific protein kinase, also known as Protein Kinase B (PKB) CCS, charcoal-stripped fetal-calf serum CSC, cancer stem cell E2, 17β-estradiol E2:ER, E2-bound estrogen receptor EGFR, epidermal growth factor receptor ER, estrogen receptor ER-P, phosphorylated estrogen receptor FCS, fetal calf serum GFR, growth factor receptor HER2, human epidermal growth factor receptor-2 MAPK, mitogen activated protein kinases mTOR, mammalian target of rapamycin NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells PI3K, phosphatidylinositide 3-kinases |
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