Accelerating Combination Drug Therapies for Triple Negative Breast Cancer through Comparative Pre-Clinical Testing of Human Xenografts and a Mouse Breast Cancer Model.

Abstract

Abstract Gene expression profiling of breast tumors identified distinct subtypes that are predictive for therapy response and overall survival. One subtype is defined as basal-like/triple-negative (TN) due to their characteristic absence of ER, PR and Her2 expression. Although a proportion of TN tumors are responsive to standard chemotherapy regimens, unresponsive tumors are aggressive, invasive, and often recur as fulminant metastatic disease. African American women have a disproportionately high incidence of TN breast cancers and they are more likely to die from the disease than Caucasians. Despite advances in the treatment of breast cancer, molecular characteristics of this subtype remain poorly understood and improved therapies are critically needed.Genomic analyses have also identified genetically engineered mouse (GEM) models that share important correlations with human breast tumor subtypes (1, 2). In particular, the C3(1)TAg GEM model appears to best represent basal-like/triple negative human breast cancers in several ways. The C3(1)TAg GEM model develops primary and metastatic mammary tumors following a progressive course characteristic of human breast tumor development: from DCIS-like (MIN) lesions to invasive mammary carcinomas (3, 4). Similar to human TN breast cancers (5), p53 and Rb functions are inactivated by T-antigen expression in C3(1)TAg mammary glands resulting in an aggressive and oncogene-relevant phenotype. In addition, both human TN and C3(1)TAg tumors have amplifications of syntenic regions (hu. Chr. 12p12; mus. Chr. 6), a region containing Ki-RAS. (2, 4, 6).We previously reported that tumors initiated by SV40 T(t)-antigen expression, including C3(1)TAg mammary tumors, carry a distinct genetic signature that is also represented in human TN breast tumors (1). The signature is enriched for DNA proliferation, damage and repair genes, suggesting that TN tumors would be responsive to commonly used cytotoxics. We hypothesize that combining drugs that target key pathways within this signature could identify new therapies and that siRNA screens may identify additional novel targets for treatment of TN tumors.We report that C3(1)Tag mammary tumor xenografts are responsive to cisplatin therapy but less responsive to paclitaxel and 5-fluorouracil as single agents. Interestingly, MDA-MB-231 xenografts, a human TN breast cancer cell line, is responsive to paclitaxel and 5-fluoruracil but not cisplatin. Differences in response between models are being explored. Combination therapies that induce DNA damage and inhibit DNA repair are also being tested. In vitro studies suggest that such combinations effectively kill cells at lower doses than used as single agents. Results of in vivo combination studies will be presented.