1. 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, (6): p
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: U54CA & U54CA132379