Mathematical modeling of cancer progression: understanding the role of RhoC GTPase in inflammatory breast cancer

ALEJANDRA C VENTURA; JACQUES-A. SEPULCHRE; MEI WU; ZHIFEN WU; JORGE R TREDICCE; SOFIA D MERAJVER

Ann Arbor, USA

Simposio; Department of Internal Medicine 2006 Research Symposium; 2006

University of Michigan, Department of Internal Medicine

Rho family members are small GTPases that are known to regulate malignant transformation and motility of cancer cells. RhoC GTPase was found to be preferentially over-expressed in inflammatory breast cancer, which is a highly aggressive form of locally advanced breast cancer that carries a guarded prognosis due to its propensity to disseminate via the dermal lymphatics and metastasize to distant organs.  It is well known that RhoC, like other GTP-binding proteins, undergoes a cycle between an active (GTP-bound) state and an inactive (GDP-bound) state, and that its switch-on/off activity is tightly regulated by activators (guanine nucleotide exchange factors, GEFs) and inactivators (GTPase-activating proteins, GAPs). We have developed a dual mathematical-experimental approach to understand this cycle and its deregulation in cancer cells in comparison with normal tissues. Using ordinary differential equations we have correlated the dynamic responses of RhoC and its regulators proteins under stimulation, with experimental data. A major impact of this work is to quantitatively predict the effects of drugs targeted against RhoC in cancer.