2. Academic Validation
  3. Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression

Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression

  • Cancer Lett. 2019 May 1:449:66-75. doi: 10.1016/j.canlet.2019.02.009.
Diana C Márquez-Garbán 1,  Manuel Gorrín-Rivas 2,  Hsiao-Wang Chen 3,  Colin Sterling Jr 4,  David Elashoff 5,  Nalo Hamilton 6,  Richard J Pietras 7
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA. Electronic address: dmarquez@mednet.ucla.edu.
  • 2 Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA. Electronic address: mjgorrin@ecaa.com.
  • 3 Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA. Electronic address: hchen@mednet.ucla.edu.
  • 4 Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
  • 5 UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA; Department of Medicine, Division of General Internal Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA. Electronic address: DElashoff@mednet.ucla.edu.
  • 6 UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA; UCLA School of Nursing, Los Angeles, CA, 90095, USA. Electronic address: nhamilton@sonnet.ucla.edu.
  • 7 Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA. Electronic address: rpietras@mednet.ucla.edu.
PMID: 30771431 DOI: 10.1016/j.canlet.2019.02.009
Abstract

Angiogenesis is critical for breast Cancer progression. Overexpression of HER-2/neu receptors occur in 25-30% of breast cancers, and treatment with trastuzumab inhibits HER-2-overexpressing tumor growth. Notably, HER-2-mediated signaling enhances vascular endothelial growth factor (VEGF) secretion to increase tumor-associated angiogenesis. Squalamine (aminosterol compound) suppresses VEGF-induced activation of kinases in vascular endothelial cells and inhibits tumor-associated angiogenesis. We assessed antitumor effects of squalamine either alone or with trastuzumab in nude mice bearing breast tumor xenografts without (MCF-7) or with HER2-overexpression (MCF-7/HER-2). Squalamine alone inhibited progression of MCF-7 tumors lacking HER2 overexpression, and squalamine combined with trastuzumab elicited marked inhibition of MCF-7/HER2 growth exceeding that of trastuzumab alone. MCF-7/HER-2 cells secrete higher levels of VEGF than MCF-7 cells, but squalamine elicited no growth inhibition of either MCF-7/HER-2 or MCF-7 cells in vitro. However, squalamine did stop growth of human umbilical vein endothelial cells (HUVECs) and reduced VEGF-induced endothelial tube-like formations in vitro. These effects correlated with blockade of focal adhesion kinase phosphorylation and stress fiber assembly in HUVECs. Thus, squalamine effectively inhibits growth of breast cancers with or without HER-2-overexpression, an effect due in part to blockade of tumor-associated angiogenesis.

Keywords

Breast cancer; MCF-7; Squalamine; Trastuzumab; Tumor-associated angiogenesis; VEGF.

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