Abstract
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody– endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.
Original language | English |
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Article number | 2904 |
Journal | Cells |
Volume | 10 |
Issue number | 11 |
DOIs | |
State | Published - 27 Oct 2021 |
Bibliographical note
Publisher Copyright:© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Funding
JDR has received funding support from the Dawn Arnall and the Roland Arnall Foundation, Morgan Pressel Foundation, Steven Dwoskin, Saul Gilinski, Bruce and Anne Rhodes, and the Sylvester Comprehensive Cancer Center. JDR has also received funding from DoD (W81XWH-11-10597, W81XWH-11-1-0598), Florida Department of Health Bankhead Coley Cancer Research Program (09BR-02). R.D. is a principal investigator, and J.D.R. and S.-U.S. are academic co-investigators on NCI/SBIR 1R43CA195882-01A1 and NIH SBIR grant 1R44 CA 265690-01A1 awarded to Synergys Biotherapeutics. MB has received support from Florida Department of Health, Bankhead-Coley Cancer Research Program: 20B14. HGH has received funding from Israel Cancer Research Fund (grant number 20-101-PG), the Israel Cancer Association (grant number 20210071), and the Israel Science Foundation (grant number 2142/21). H.G.-H. and J.D.R. have received joint funding from Professor Moshe I. Meidar, Hilit-Meidar Alfi Ph.D., Eyal Alfi, Liad Meidar.
Funders | Funder number |
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Bankhead-Coley Cancer Research Program | 20B14 |
Dawn Arnall | |
Morgan Pressel Foundation | |
NIH SBIR | 1R44 CA 265690-01A1 |
Roland Arnall Foundation | |
Sylvester Comprehensive Cancer Center | |
U.S. Department of Defense | W81XWH-11-1-0598, W81XWH-11-10597 |
National Cancer Institute | 20210071 |
Israel Cancer Research Fund | 20-101-PG |
Small Business Innovation Research | 1R43CA195882-01A1 |
Florida Department of Health | 09BR-02 |
Israel Science Foundation | 2142/21 |
Keywords
- EGFR
- Endostatin
- Triple negative breast cancer
- Vasculogenic mimicry