M. Okano1, E. Katsuta1, M. Oshi1, X. Peng2, L. Yan2, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Biostatistics & Bioinformatics,Buffalo, NY, USA
Introduction: Annexin A1 (ANXA1) is a phospholipid-linked protein, is known to have multiple functions related to inflammatory pathways, cell proliferation and the regulation of cell death signaling. ANXA1 was reported to have some association with cancer development, but the role of ANXA1 seems different depends on cancer types. Recently, we reported that ANXA1 is associated with triple-negative breast cancer (TNBC) and its poor prognosis in 211 Japanese breast cancer cases. Some reports similarly that ANXA1 high expressed breast cancer has poor survival. On the other hand, there are some studies demonstrating opposite results with high ANXA1 expression being associated with better outcome. It is speculated that the breast cancer subtypes may be one of the reasons for these controversial results. In this study, we investigated the association of ANXA1 mRNA/protein expression and patient survival in each subtype using gene and protein expression data of the publically available large cohort.
Methods: Clinical, RNA-seq and Reverse Phase Protein Array (RPPA) data were obtained from the Cancer Genome Atlas (TCGA). Overall survival (OS) and Gene set enrichment analysis (GSEA) were conducted comparing high and low expression group.
Results:Among ER positive and HER2 positive patients, low mRNA expression of ANXA1 group has significantly worse OS (p=0.004, p=0.005, respectively). On the other hand, high mRNA expression of ANXA1 group showed significantly worse OS (p=0.028) in TNBC patients. In analysis using RPPA data, OS was significantly shorter in patients with high ANXA1 tumors among ER positive patients and HER2 positive patients (p<0.001, p=0.016, respectively) but high ANXA1 group has worse OS in TNBC patient (p=0.0095), which were in agreement with transcriptome analysis. To explore the mechanism of these results, GSEA was conducted. In TNBC patients, high ANXA1 expression tumors were enriched EMT related genes (NES=1.916, p=0.004), IL2/STAT5 (NES=2.04, p=0.003) and TNF-α signaling related genes (NES=2.02, p=0.011). On the other hand, in ER positive and HER2 positive patients, high ANXA1 expression tumors were enriched apoptosis related genes (NES=2.30, p<0.01) and p53 pathway related genes (NES=2.08, p<0.01).
Conclusion:We demonstrate high expression of ANXA1 enriched EMT signaling related gene expression in TNBC patients that associated with worse OS. On the other hand, in ER positive patients and HER2 positive patients, high ANXA1 expression is associated with better progression and the possible reason of this outcome is the apoptosis and p53 pathway. This discrepancy between ER positive breast cancer and TNBC on the effect of ANXA1 expression on patient survival might exemplify the fact that these subtypes possess significantly deferent molecular/genetic backgrounds.