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.
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.
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.
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.
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The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Protein kinase B
Dulbecco’s Modified Eagle Medium
Extracellular signal-regulated protein kinases 1 and 2
Focal adhesion kinase
Fetal bovine serum
Hepatocyte growth factor receptor
Horse radish peroxide
Institutional Animal Care and Use Committee
Intercellular Adhesion Molecule 1
Immunoglobulin Fc region
Mitogen-activated protein kinase
Phosphate buffer saline
Standard error of the mean
Sodium dodecyl sulfate
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
Standard of care
Triple negative breast cancer
Tris-buffered saline with Tween-20
Tumor necrosis factor receptor-2
- V t/V o :
Tumor volume on Day t over tumor volume on Day 0
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We thank Dr. William S. Twaddell (School of Medicine, University of Maryland, Baltimore) for assisting in animal tumor section evaluation and Dr. Young Suk Lee (University of Maryland, Baltimore) for her review and suggestions on animal data. We also thank Drs. Rena Lapidus, Antonino Passaniti and Amy Fulton (School of Medicine, University of Maryland, Baltimore) for their suggestions and kind review of the manuscript. This work was supported by grant R44 CA 224718 from the National Cancer Institute to GS.
This work was supported by grant R44 CA 224718 from the National Cancer Institute to Ginette Serrero’s laboratory.
Conflict of interest
Binbin Yue, Jianping Dong, and Ginette Serrero are employees of A&G Pharmaceutical. Rupa Guha and Aditi Banerjee have no conflicts to declare.
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Guha, R., Yue, B., Dong, J. et al. Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration. Breast Cancer Res Treat (2021). https://doi.org/10.1007/s10549-021-06120-y
- Triple negative breast cancer
- Anti-progranulin antibody
- Progranulin SiRNA