Abstract
Studies from our laboratory have explained that breast tumor progression can be attenuated by targeting the N-linked glycoproteins of the tumor microvasculature and that of tumor cells alike with a protein N-glycosylation inhibitor, tunicamycin. Absence of N-glycosylation leads to an accumulation of un- or mis-folded proteins in the ER and the cell develops “ER stress”. The result is cell cycle arrest, and induction of apoptosis mediated by unfolded protein response (upr) signaling. Tunicamycin inhibited in vitro and in vivo (Matrigel™ implants in athymic nude mice) angiogenesis in a dose dependent manner. The action is irreversible and survived under tumor microenvironment, i.e., in the presence of FGF-2 or VEGF or higher serum concentration. Importantly, tunicamycin prevented the progression of double negative (ER-/PR-/Her2+) and triple negative (ER-/PR-/Her2-) breast tumors by ∼55% - 65% in three weeks in athymic nude mice [Balb/c(nu/nu)]. Analyses of paraffin sections exhibited “ER stress” in both microvasculature and in tumor tissue.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / blood supply
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA Fragmentation / drug effects
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum Stress / drug effects
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Female
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Humans
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Mice, Nude
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Neovascularization, Pathologic / prevention & control
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Phosphorylation / drug effects
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Spectrum Analysis, Raman
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Time Factors
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Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors*
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Transferases (Other Substituted Phosphate Groups) / metabolism
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Tumor Burden / drug effects
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Tunicamycin / pharmacology*
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Xenograft Model Antitumor Assays*
Substances
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Tunicamycin
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Transferases (Other Substituted Phosphate Groups)
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UDPacetylglucosamine-dolichyl-phosphate acetylglucosamine-1-phosphate transferase