The Role of TIPE2 Protein in Invasive Breast Carcinoma By Frances Maher University of Pennsylvania Coordinating Center: Stanford University

Outline Introduction Central Hypothesis Specific Studies Conclusions Invasive Breast Carcinoma Invasive Breast Carcinoma and the Immune System TIPE2 Central Hypothesis Specific Studies Conclusions

Invasive Breast Carcinoma Results from uncontrolled cell growth in the lobule (milk-producing glands) and lactiferous duct (channels that transport milk) Second leading cause of cancer death among women and 1 in 8 US women will be diagnosed with invasive breast cancer The need for improved therapeutic approaches is urgent and crucial American Cancer Society, 2016 U.S. National Library of Medicine, 2015

Invasive Breast Carcinoma and the Immune System Acute inflammatory response TH-1 Leukocyte Tumor Cytotoxicity- Toxic to tumor cells Tumor destruction Macrophage Polarization- When a macrophage activates different functions based on the molecular environment Leukocytes- White blood cell that defends foreign molecules and disease Macrophage- White blood cell that digests cellular/foreign wastes DeNardo. et al. Breast Cancer Research (2007) 9:212

Tumor Rejection

Invasive Breast Carcinoma and the Immune System Chronic inflammatory response TH-2 Leukocyte and T Regulatory Cell (Leukocyte) Angiogenesis- Production of new blood vessels Secretes anti-inflammatory factors Promotes Tumor Microenvironment Anti-Inflammatory Factors- Substance that turns off immune response Leukocytes- White blood cell that defends foreign molecules and disease DeNardo. et al. Breast Cancer Research (2007) 9:212

Tumor Promotion

TIPE2 Tumor necrosis factor-α-induced protein like-2 Regulator of inflammation and immune homeostasis Inhibitor in lung and colon cancer ________ in breast cancer Honghong, S. et al. Cell. (2008) 133(3):415-426

MAIN HYPOTHESIS TIPE2 is involved in invasive breast carcinoma progression by regulating the immune response

Study 1: Determine the survival rates among breast cancer patients with varying TIPE2 mRNA expression

Invasive Breast Carcinoma Survival Rates Patients with HIGH TIPE2 Patients with LOW TIPE2 (Sample Size: 1105 patients) Oncolnc Analysis TCGA, Cell 2012

Study 2: Determine the expression levels of TIPE2 mRNA in different types of cancer cell lines

TIPE2 mRNA Cancer Cell Line Analysis Immune-related cancers Non-immune related cancers CCLE Analysis

Study 3: Determine the pathway that TIPE2 is involved in during breast cancer progression

Genes Coexpressed with TIPE2 in Invasive Breast Carcinoma Pearson’s Correlation- Linear correlation between two variables CD-4 TIPE2 Brady, RL. Science. (1993) 260 (5110): 979–83. TCGA, Cell 2015

Pathways of Genes Coexpressed with TIPE2 in Breast Cancer Gene Set Enrichment Analysis- Aims to find genes correlated with disease phenotypes by pinpointing specific genes that are overrepresented in a group of genes. Immune-related pathways/processes ClueGO Analysis

Conclusions Upregulation of TIPE2 mRNA is correlated with favorable patient prognosis in breast cancer TIPE2 gene expression is associated with immune functions in breast cancer TIPE2 may serve as a novel prognostic biomarker and therapeutic target for invasive breast cancer

Correlated with Immune Cell Functions and Migration in Breast Cancer Increased TIPE2 mRNA Correlated with Immune Cell Functions and Migration in Breast Cancer Higher Survival

Thank You for your time!

Acknowledgements University of Pennsylvania Stanford University Dr.Halpern-Felsher Dr.Li Ms.McLaughlin Dr.Chen Dr.Cathopoulis National Institutes of Health STEP-UP Dr.Rivers