title: Modeling the estrogen receptor to growth factor receptor signaling switch in human breast cancer cells.
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.
authors.affiliation: Graduate Program in Genetics, Bioinformatics and Computational Biology, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.forename: William T
authors.initials: WT
authors.lastname: Baumann
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: John J
authors.initials: JJ
authors.lastname: Tyson
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008962:Models, Theoretical; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D004967:Estrogens; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: 17β-estradiol; AKT; Breast cancer; CCS; CSC; E2; E2-bound estrogen receptor; E2:ER; EGFR; ER; ER-P; Endocrine resistance; Estrogen receptor signaling; FCS; GFR; Growth factor receptor signaling; HER2; MAPK; Mathematical modeling; NFκB; PI3K; a serine/threonine-specific protein kinase, also known as Protein Kinase B (PKB); cancer stem cell; charcoal-stripped fetal-calf serum; epidermal growth factor receptor; estrogen receptor; fetal calf serum; growth factor receptor; human epidermal growth factor receptor-2; mTOR; mammalian target of rapamycin; mitogen activated protein kinases; nuclear factor kappa-light-chain-enhancer of activated B cells; phosphatidylinositide 3-kinases; phosphorylated estrogen receptor