P4-03-06: Development and Comparative Characterization of Metastasis in Newly Developed Pre-Clinical Models of Inflammatory Breast Cancer.
Authors: Chu K , Mu Z , Alpaugh KR , Fernandez S , Freiter EM , Wu H , Zook MB , Barsky SH , Cristofanilli M , Robertson FM 
Published: June 2012

Background: Inflammatory breast cancer (IBC) is the most metastatic variant of breast cancer. It is associated with a poor survival rate (40% 5-year survival) despite appropriate multidisciplinary care. For such an aggressive type of cancer, IBC has been understudied, in part due to the lack of adequate numbers of cell lines and mouse models that recapitulate the human disease. To expand our understanding of IBC, we have obtained all of the previously developed and characterized IBC cell lines and models including Mary-X, SUM149, SUM190, KPL-4, MDA-IBC-3 and have developed two new IBC models, designated as FC-IBC01 and FC-IBC02, using tumor cells derived from pleural effusion of IBC patients.

Materials and Methods: Each of these IBC cell lines has been luciferase (LUC)-tagged, allowing the growth of orthotopic injection or subcutaneous implantation to be evaluated by bioluminescent imaging (BLI). Alternatively, the LUC-tagged IBC cells can by injected via either intra-cardiac or intravenous route of delivery, which promotes rapid tumor colonization, resulting in both visceral and skeletal metastasis. Growth of IBC tumors can then be monitored immediately using BLI, thus eliminating the lag time needed for the physical detection of palpable tumors. BLI imaging also allows for monitoring of the kinetics and location of development of metastatic lesions. Whole transcriptome analysis was performed on IBC cell lines and xenograft tissues to define the heterogeneity of IBC as a distinct variant of breast cancer

Results: These models have allowed us to identify micro-metastatic foci in multiple sites distant from the IBC primary tumor in each of these models of IBC and allow the quantitation of anti-tumor and anti-metastatic effects of targeted therapeutics as single agents as well as the potential synergy of combinations of agents. As an example, injection of LUC-tagged IBC cell lines such as SUM149-Luc, into the left ventricle of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice allows the metastatic tumor burden to be monitored longitudinally by whole animal BLI, which can be validated at necropsy and by immunohistochemical analysis. Whole transcriptome analysis of pre-clinical models of IBC reflect the molecular subtypes observed in IBC patients, with the majority of IBC models being of the basal like, luminal B and Her2 amplified. Discussion: First time analysis of known and newly developed pre-clinical models of IBC allows a more complete analysis of IBC as a distinct variant of breast cancer. Furthermore, these approaches allow rapid evaluation of the promising targeted therapeutics identified based on whole transcriptome analysis of both IBC patient tumors and pre-clinical models developed from IBC patients. We believe that this extensive collection of LUC-tagged IBC cell lines is an invaluable tool for IBC research since the cell lines encompass the broad spectrum of IBC heterogeneity.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-03-06.