Rupa Guha1,2, Binbin Yue1, Jianping Dong1, Aditi Banerjee3, Ginette Serrero4,5. 1. A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA. 2. Graduate Program in Life Sciences, University of Maryland School of Medicine, 655 W. Baltimore St, Baltimore, MD, 21201, USA. 3. Department of Pediatrics, University of Maryland School of Medicine, 655 W. Baltimore St, Baltimore, MD, 21201, USA. 4. A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA. gserrero@agpharma.com. 5. University of Maryland Greenebaum Comprehensive Cancer Center, 22 S. Greene St, Baltimore, MD, 21201, USA. gserrero@agpharma.com.
Abstract
BACKGROUND: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC. METHODS: The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo. RESULTS: Inhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo. CONCLUSION: PGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.
BACKGROUND: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC. METHODS: The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo. RESULTS: Inhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo. CONCLUSION: PGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.
Entities:
Keywords:
Anti-progranulin antibody; Ki67; Migration; Progranulin SiRNA; Progranulin/GP88; Proliferation; Triple negative breast cancer
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