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.
Author Summary Iron is required for cellular metabolism and growth, but can be toxic due to its ability to cause high oxidative stress and consequently DNA damage. To prevent damage, all organisms that require iron have developed mechanisms to tightly control iron levels. Dysregulation of iron metabolism is detrimental and can contribute to a wide range of diseases, including cancer. This paper presents a predictive mathematical model of iron regulation linked to iron utilization, oxidative stress, and the oncogenic response specific to normal breast epithelial cells. The model uses a discrete modeling framework to generate novel biological hypotheses for an investigation of how normal breast cells become malignant cells, capturing a breast cancer phenotype of iron homeostasis through overexpression and knockout simulations. The new biology discovered is (1) IRP2 overexpression alters the iron homeostasis pathway in breast cells, without affecting the oxidative stress response or oncogenic pathways, (2) an activated oncogenic pathway disrupts iron regulation in breast cancer cells.