A Functional Map of Oncogenic States for Breast Cancer Nina Ly1,2, Oliver Harismendy2, Kate Medetgul-Ernar2, Huwate (Kwat) Yeerna,2 Elena Martinez2, and Pablo Tamayo2 1San Diego State University and 2University of California San Diego Moores Cancer Center Introduction Breast cancer is one of the most common cancers worldwide and is one of the leading causes of death next to lung cancer. Treatment is dependent on the molecular features and/or genomic characteristics of each tumor subtype. It is important to classify breast cancer to understand their functional similarities and differences. Accurately identifying breast cancer cellular states is crucial in order to understand how to treat patients efficiently and effectively. In order to do so, we created a functional map of oncogenic states that can be used to categorize and characterize the viable cellular states that arise in primary-untreated or post-treatment cancers. We applied Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework, to help organize the cell lines onto a reference map defined by their cellular states. The Onco-GPS has revealed 9 different oncogenic states. Figure 1: Schematic illustrating various breast cancer subtypes. The blue and pink rectangles group the subtypes based on the expression of estrogen receptor (ER)/Progesterone (PR), positive in the blue (Luminal A and Luminal B) and negative (HER2+ and basal-like) in the pink. The central grey rectangle (with black outline) indicates the presence of HER2 amplification in Luminal B and HER2+ subtypes. [1] Methods Pathways II. Synthetic Lethality Results Interferon Alpha Response Stimulate multifaceted antitumor immunity BZRAP1 Potential peptide vaccine against human breast cancer SMC1A Maintains and screens for defects in sister chromatids State 3 vs. Pathways STATE 3 State 3 vs. Synthetic Lethality III. Drug Sensitivity State 3 Saracatinib SRC inhibitor PD318088 MEK1 inhibitor IV. Mutations CDH6 Controls cellular architecture BRCA1 & BRCA2 Provides instructions for tumor suppressor proteins Involved in DNA repair State 3 vs. Drug Sensitivity STATE 2 State 3 Pathways II. Synthetic Lethality State 3 vs. Mutation V. Gene Expression BTBD9 Protein-protein interactions EMT Epithelial Mesenchymal Transition PARP14 Promotes aerobic glycolysis (Warburg effect) to support anabolic growth and evade apoptosis State 2 vs. Synthetic Lethality VI. Protein State 2 P-Cadherin P-Cadherin over expression is mainly found in the triple-negative/basal-like subgroup of breast cancers Strongly correlated with the presence of BRCA1 mutations MEK1 Part of a signaling pathway called the RAS/MAPK pathway State 2 vs. Pathways State 2 State 3 vs. Gene Expression State 3 III. Drug Sensitivity IV. Mutations Birinapant Binds to and inhibits the activity of IAP (Inhibitor of Apoptosis Protein) CADPS Encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretory vesicles Here, we created a functional map for breast cancer by applying Onco-GPS (OncoGenic Positioning System to help generate a two-dimensional map of the functional states that these components define. We decomposed a collection of breast cancer cell lines into 9 transcriptional components, and used these components to generate an Onco-GPS layout. We then used an information-theoretic measure of association to match the Onco-GPS transcriptional components against genome-wide datasets State 2 vs. Drug Sensitivity State 3 vs. Protein State 2 State 3 State 2 vs. Mutation State 2 V. Gene Expression VI. Proteins Conclusion ZEB2 Mediate the repression of E-cadherin expression in HER2 breast cancer cells The Onco-GPS map provides an intriguing perspective on breast cancer and the complexity of oncogenic activation. We hope to be able to validate the drug sensitivity experimentally and analyze human samples such as those in the Cancer Genome Atlas. Fibronectin Breast carcinomas with distant metastasis frequently have tumor cells expressing intracellular Fibronectin State 2 vs. Gene Expression State 2 vs. Protein References Kim, W. J., et al. Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States, Cell Systems 2017 in press. Sandhu, R., et al., Microarray-based gene expression profiling for molecular classification of breast cancer and identification of new targets for therapy. Lab Medicine, 2010. 41(6): p. 364-372. State 2 State 2 Research reported in this poster was supported by the National Cancer Institute of the National Institutes of Health under award numbers: U54CA132384 & U54CA132379