HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

Oncogene. 2012 Apr 5;31(14):1757-70. doi: 10.1038/onc.2011.365. Epub 2011 Aug 22.


Most cases of breast cancer (BrCa) mortality are due to vascular metastasis. BrCa cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor (HIF) activity in BrCa cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of BrCa cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of BrCa cells to ECs. Interference with HIF, ANGPTL4 or L1CAM expression inhibits vascular metastasis of BrCa cells to the lungs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-like Proteins
  • Angiopoietins / metabolism*
  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Lung Neoplasms / secondary*
  • Mice
  • Neoplasm Transplantation
  • RNA Interference
  • Spermidine / analogs & derivatives*
  • Spermidine / metabolism


  • ANGPTL3 protein, human
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Hypoxia-Inducible Factor 1
  • N,N',N''-tris(2,3-dihydroxy-5-sulfobenzoyl)-1,5,10-triazadecane
  • Spermidine