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Updated: May 18, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
ADAM-17: a novel therapeutic target for triple negative breast cancer
P M McGowan1, M Mullooly1, F Caiazza1
1Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
Background:
Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors.
Patients And Methods:
Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs.
Results:
In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents.
Conclusion:
It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.
Insights
Targeted therapy for triple-negative breast cancer is lacking. Inhibiting ADAM-17 protease, which is highly expressed in TNBC, shows promise in blocking cancer cell proliferation and enhancing treatment responses.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) lacks validated targeted therapies.
- ADAM-17 protease is implicated in EGFR/HER family signaling pathways.
Purpose of the Study:
- To investigate ADAM-17 expression in breast cancer subtypes.
- To evaluate the therapeutic potential of an ADAM-17 inhibitor in breast cancer models.
Main Methods:
- ADAM-17 expression analysis via Western blotting and immunohistochemistry.
- Assessment of the ADAM-17 inhibitor PF-5480090 in breast cancer cell lines.
- Correlation analysis between ADAM-17 activity and proliferation inhibition.
Main Results:
- Significantly higher ADAM-17 levels were observed in TNBC compared to non-TNBC.
- PF-5480090 reduced EGFR ligand release, decreased EGFR phosphorylation, and inhibited cell proliferation.
- A strong correlation was found between ADAM-17 activity and PF-5480090 efficacy.
- PF-5480090 pretreatment enhanced sensitivity to chemotherapy and anti-EGFR/HER agents.
Conclusions:
- ADAM-17 inhibition represents a potential therapeutic strategy for breast cancer, including TNBC.
- Combination therapy with ADAM-17 inhibitors and chemotherapy or anti-EGFR/HER agents may improve treatment outcomes.
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