Abstract 2307: Targeted agents and chemotherapeutic treatments of genetically engineered Basal-like breast cancer mouse model

Abstract

Abstract Background: Genomic characterization of human breast tumors has resulted in the identification of at least five distinct tumor subtypes (Luminal A and B, HER2-enriched, Claudin-low, and Basal-like). These subtypes each show their own unique biology, which correlates with distinct patient outcomes. Basal-like Breast Cancer (BLBC) is associated with high grade, BRCA1 mutation status, younger patient age, and increased frequency in African Americans. In order to identify novel therapeutic strategies for BLBC, we developed a genetically engineered mouse model based upon two common human BLBC genetic events, namely BRCA1 and TP53 loss. Results: We developed a genetically engineered mouse (GEM) model of breast cancer by inactivating TP53 and BRCA1 genes using Cre-LOX technology in the mammary gland (K14-cre / TP53 L/L / BRCA1 L/L). As part of the characterization of this GEM model, we performed gene expression profiling and DNA copy number analysis using aCGH arrays on the Basal-like tumors from this model (25/27 total tumors were Basal-like). We found a number of chromosomal regions that were similarly altered and found to be specific to mouse and human BLBC including gains of mouse chromosome 1q and 12q and losses in chromosomes 3F1 and 15q. Subsequently two tumors from the murine Basal-like group were taken and expanded into an orthotopic syngeneic model where they passaged in wild type FVB mice. These two tumors lines were then tested extensively with chemotherapeutics (Doxorubicin, Carboplatin, Cytoxan, Paclitaxel) and biologically targeted agents (MEK inhibitor/AZD6244, PI3K Inhibitor/BEZ235, PARP Inhibitor/ABT888 and mTOR Inhibitor/Everolimus). The DNA damaging agents exhibited exceptional efficacy (i.e. ABT888, Cytoxan, and Carboplatin), whereas the biologically targeted agents tended to at best, only slow tumor growth, even in combination. Conclusions: Genetic engineering of mice using TP53 and BRCA1 loss results in tumors of predominantly the Basal-like subtype phenotype. As expected, these tumors were exquisitely sensitive to DNA damaging chemotherapeutics including cytoxan and carboplatin, yet generally insensitive to the 3 tested kinase inhibitors. Novel combinations of targeted agents and chemotherapeutics are now being tested. Citation Format: Cristina M. Contreras, Grace O. Silva, Adam D. Pfefferle, Charles M. Perou. Targeted agents and chemotherapeutic treatments of genetically engineered Basal-like breast cancer mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2307. doi:10.1158/1538-7445.AM2015-2307