P2-01-16: Dissecting the Cellular Mechanism of Induction and Sustenance of Dormancy by Rho GTPases in Breast Cancer.

Abstract

Abstract Tumor dormancy has been a very real problem in breast cancer survivors where recurrences are common and usually fatal. Molecular mechanisms involved in this process are often poorly understood and are a hot spotin breast cancer research today. We have found that Rho GTPases, specifically RhoC, is hyperactivated in low metastatic dormant breast tumor cells while RhoA is downregulated. We also found RhoC causes phosphorylation of c-jun NH2 terminal kinase (JNK) in these cells which in turn activates the process of autophagy, a possible mode of cell survival in dormant tumor cells. Modulating RhoC affected phosphorylation of JNK. Also, abrogating JNK by a pharmacological inhibitor SP600125 inhibited expression of the autophagy marker LC3B-II. Autophagy genes like Atg 5 and Atg 12 were expressed along with the autophagy marker LC3B-II. On inhibiting autophagy by a specific inhibitor 3-Methyladenine (3-MA), cells did not readily undergo apoptosis but on stressing them doubly with LY294002, an inhibitor of Class I PI3K, along with 3-MA (inhibitor of Class III PI3K), significant number of dormant cells underwent apoptosis as observed by TUNEL staining. We also found that p190RhoGAP was activated in these dormant cells which may lead to the observed downregulation of RhoA activation levels. Involvement of beta-1 integrin along with c-src in activation of RhoC was observed in these dormant cells. We are in the process of further elucidating these signal transduction processes that might be involved in cellular dormancy of breast cancer. A better understanding of some of the cellular mechanisms of induction and sustenance of dormancy may aid in formulating therapies for annihilating these dormant tumor cells thus preventing the often fatal relapses in breast cancer survivors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-16.