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Modified Yeast-Two-Hybrid System to Identify Proteins Interacting with the Growth Factor Progranulin
Published on: January 17, 2012
Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration
Rupa Guha1,2, Binbin Yue1, Jianping Dong1
1A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA.
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.
Insights
Blocking progranulin (PGRN/GP88) with antibody AG01 shows promise for treating triple-negative breast cancer (TNBC). This targeted approach reduced tumor growth and migration, offering potential new therapies for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) presents significant challenges due to its invasiveness and poor prognosis.
- Progranulin (PGRN/GP88) is implicated in cancer progression, survival, and drug resistance, with elevated levels linked to adverse outcomes.
- PGRN/GP88 is overexpressed in approximately 30% of TNBC cases, highlighting its potential role in this subtype.
Purpose of the Study:
- To investigate the role of progranulin (PGRN/GP88) in TNBC.
- To evaluate the therapeutic potential of targeting PGRN/GP88 in TNBC models.
Main Methods:
- Investigated the effect of inhibiting PGRN/GP88 expression using siRNA in TNBC cells.
- Examined the impact of a neutralizing anti-PGRN/GP88 monoclonal antibody (AG01) on TNBC cell proliferation and migration in vitro.
- Assessed the efficacy of AG01 in vivo using TNBC cell lines.
Main Results:
- Inhibition of PGRN/GP88 via siRNA and AG01 treatment dose-dependently reduced proliferation and migration in MDA-MB-231 and HS578-T TNBC cell lines.
- AG01 treatment decreased the expression of phosphorylated protein kinases (p-Src, p-AKT, p-ERK).
- In vivo studies demonstrated inhibition of tumor growth and reduced Ki67 expression following AG01 treatment.
Conclusions:
- PGRN/GP88 is identified as a viable therapeutic target for TNBC, potentially with companion diagnostics.
- Antibody-mediated blockade of PGRN/GP88 (AG01) offers a promising novel therapeutic strategy for TNBC.
- This approach may overcome limitations of standard-of-care therapies, including toxicity and unresponsiveness.
