Short-term dynamics of RhoC GTPase in aggressive phenotypes of breast cancer

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

Ann Arbor, USA

Simposio; Department of Internal Medicine 2008 Research Symposium; 2008

University of Michigan, Department of Internal Medicine

 The most damaging change during cancer progression is the growth of metastases. The protein RhoC GTPase was found to be crucial in that process in different cancers, particularly, in a highly aggressive form of breast cancer, termed inflammatory breast cancer (IBC). RhoC is a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states, tightly regulated by several regulatory proteins. We have developed a dual mathematical-experimental approach to understand this cycle and its deregulation in breast cancer cells in comparison with normal ones. A major impact of this work is to quantitatively predict the effects of drugs targeted against RhoC in cancer.      We have found that the activation profile of RhoC after stimulation with lysophophatidic acid (LPA) is similar to those of other small GTPases. Unexpectedly however, a significant and rapid increase in RhoC protein abundance accompanies this activation profile. We have found that this increase is due to a previously unrecognized feedback loop between the activation cycle and the protein synthesis-degradation balance. We have studied this atypical behavior in detail. The correlation of this novel finding with the aggressiveness of IBC cells is unveiled, as well as its impact in drug strategies.