Abstract ES8-1: Inflammation and Breast Cancer

Abstract

Abstract Mechanism-based insights into prognosis and treatment of breast cancer derived from high resolution multiphoton imaging John Condeelis, Thomas Rohan, Maja Oktay - Einstein, New York; Tony Ng – King's College London, UK; Seema Agarwal, David Rimm – Yale, New Haven; Brian Robinson, Joan Jones – Weill Cornell Medical Center, New York Frank Gertler MIT, Boston. Multi-photon microscopy allows the observation of tumor cell behavior at single cell resolution in vivo and has demonstrated that invasive and migratory tumor cells in mammary tumors form migratory streams and intravasate only when associated with macrophages. This analysis demonstrates that tumor cell streaming and intravasation are cell autonomous behaviors that are the direct result of the tumor cell -macrophage interaction. The in vivo invasion assay was developed to collect these streaming and intravasation competent tumor cells from primary tumors in vivo. Collection of these cells was coupled to expression profiling to reveal the genes expressed by tumor cells during streaming and intravasation in rat, mouse and human breast tumors (the Invasion Signature). The invasion, adhesion and motility pathways identified in the Invasion Signature converge on the RhoC/Cofilin/Mena pathway identifying it as a master regulator of chemotaxis, streaming and intravasation of breast tumor cells in vivo. Using prognostic markers derived from the RhoC/Cofilin/Mena pathway, anatomical landmarks have been developed for use with breast cancer patients. One of these, composed of the tumor cell-macrophage intravasation complex, is called TMEM (Tumor MicroEnvironment for Metastasis) in human breast tumors. TMEM density in histology sections of breast tumor tissue has been found to predict metastatic risk. The potential for tumor cell/macrophage pairing, steaming and TMEM assembly can be detected in breast tumors by the relative expression of isoforms of Mena-INV (enhancer) and Mena11a (suppressor of migration and dissemination, referred to as the MenaCalc test). Two retrospective studies with breast cancer tissue from patients with known recurrence and survival outcome have demonstrated the use, for prediction of metastatic risk, of the MenaCalc test and the TMEM test in resected breast tumor tissue. A CofilinxP-Cofilin test, also derived from the RhoC/Cofilin/Mena pathway of the human Invasion Signature, is showing promise as a predictor of disease-free survival. The Cofilin part of the RhoC/Mena/Cofilin pathway is associated with the overall activity of a biologically relevant sub-network of proteins (centered around four seed proteins ezrin/radixin/moesin/cofilin) in the cancer proteome that control membrane-cytoskeletal linkage and tumor cell motility. CofilinxP-Cofilin co-localization intensity was the most biologically significant variable measured among these others in predicting survival in a large retrospective trial of breast cancer patients. The value of this test derives from the fact that it is independent of anti-estrogen (hormonal) treatment and chemotherapy. In summary, multi-photon imaging in deep tissue locations in live animals in real time has revealed molecular mechanisms associated with complex cancer cell behavior during metastatic dissemination leading directly to new markers of metastatic risk and survival. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES8-1.