Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective.
Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built.
Department of Mathematics and Statistics, American University, Washington, DC, USA.
Julia
0000-0002-7520-0627
J
Chifman
The Jackson Laboratory, Bar Harbor, ME, USA.
Seda
0000-0002-3988-1947
S
Arat
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
Zhiyong
0000-0001-9761-9720
Z
Deng
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
Erica
E
Lemler
Chemical and Physical Biology Graduate Program, Vanderbilt University, Nashville, TN, USA.
James C
0000-0001-9882-6748
JC
Pino
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Leonard A
0000-0003-2112-6940
LA
Harris
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
Michael A
MA
Kochen
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.|Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.|Center for Quantitative Science, Vanderbilt University, Nashville, TN, USA.
Carlos F
0000-0003-3668-7468
CF
Lopez
Cancer Program, Roper St Francis HealthCare, Charleston, SC, USA.
Steven A
SA
Akman
Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.
Frank M
FM
Torti
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
Suzy V
SV
Torti
Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, CT, USA.|The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Reinhard
R
Laubenbacher
D000222:Adaptation, Physiological; D000818:Animals; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003198:Computer Simulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D007501:Iron; D018631:ras Proteins; D035942:Iron Regulatory Protein 2