Abstract 5200: High CD73 expression, regulated by estrogen signaling, associates with cancer aggressiveness in estrogen receptor (+) breast cancer

Abstract

Abstract Background: CD73, a cell surface enzyme, catalyzes the generation of adenosine from ATP and ADP in the tumor microenvironment along with CD39. Accumulated extracellular adenosine functions as immune-suppressor, and also binds to adenosine receptors which promotes angiogenesis and cell proliferation that results in accelerate cancer progression. However, the clinical significance and molecular function of CD73 expression in breast cancer remains unclear. Methods: Utilizing breast cancer cohorts of TCGA and GEO, clinical significance and underlying mechanisms were investigated. Molecular experiments were carried out in MCF7 cells, ER(+) breast cancer cell line. Results: In TCGA cohort, CD73 expression level was significantly lower in ER(+) breast cancers compared to ER(-) tumors. Higher CD73 expression was associated with worse overall survival in ER(+) tumors (p=0.003), but not in ER(-) tumors. Gene Set Enrichment Analysis revealed that estrogen response gene sets (Early; p=0.043, Late; p=0.021) were significantly enriched in CD73 low expressing ER(+) tumors, suggesting estrogen signaling may repress CD73 expression. To test this hypothesis, we analyzed the expression of CD73 and CD39 in MCF7 cells treated with estrogen, tamoxifen. Our data revealed that estrogen treatment suppressed CD73 and CD39 expression, whereas tamoxifen treatment enhanced expression of the genes. These findings suggest that CD73 and CD39 gene expression is suppressed by estrogen signaling, whereas binding of ER antagonists such as tamoxifen can remove the repressive effect on gene expression. On the other hand, epithelial-mesenchymal transition (EMT) (p<0.001) and angiogenesis (p<0.001) gene sets were significantly enriched in CD73 high expressing ER(+) tumors. CIBERSORT demonstrated that CD73 high expressing ER(+) tumors have less infiltrating CD8(+) T cells, memory B cells and plasma cells, implying that CD73 high expressing tumors have immune suppressive environment, which is in agreement with the notion that CD73 high tumors are immunosuppressive. Finally, we found that CD73 expression was significantly elevated post-chemotherapy compared to tumors prior to the treatment (p=0.007), and CD73 high expression patients showed worse relapse-free survival in neoadjuvant chemotherapy patients cohort (p=0.003). Conclusion: Molecular studies revealed that CD73 expression is regulated by estrogen signaling. Increased expression of CD73 significantly correlates with worse outcomes in ER(+) breast cancer patients. This may be due to upregulated pro-metastatic gene signatures such as EMT and angiogenesis as well as less infiltration of anti-cancer immune cells by adenosine generated by CD73 in the tumor microenvironment. Our data reveals an intriguing mechanism which may be responsible for recurrence and metastasis of ER(+) breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Eriko Katsuta, Vivek Anand, Li Yan, Subhamoy Dasgupta, Kazuaki Takabe. High CD73 expression, regulated by estrogen signaling, associates with cancer aggressiveness in estrogen receptor (+) breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5200.