Molecular hierarchy of heparin-binding EGF-like growth factor-regulated angiogenesis in triple-negative breast cancer.

Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under two-dimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1α and NF-κB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis.
AuthorsFusanori Yotsumoto, Eriko Tokunaga, Eiji Oki, Yoshihiko Maehara, Hiromi Yamada, Kyoko Nakajima, Sung Ouk Nam, Kohei Miyata, Midori Koyanagi, Keiko Doi, Senji Shirasawa, Masahide Kuroki, Shingo Miyamoto
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 5 Pg. 506-17 (May 2013) ISSN: 1557-3125 [Electronic] United States
PMID23443317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2013 AACR.
Chemical References
  • ANGPTL4 protein, human
  • Angiopoietins
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Angiopoietins (genetics, metabolism)
  • Animals
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins (genetics, metabolism)
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neovascularization, Pathologic (genetics, metabolism, pathology)
  • Phosphorylation
  • Signal Transduction
  • Transfection
  • Triple Negative Breast Neoplasms (blood supply, genetics, metabolism)
  • Vascular Endothelial Growth Factor A (genetics, metabolism)
  • Xenograft Model Antitumor Assays

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