Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis

Proc Natl Acad Sci U S A. 2021 May 11;118(19):e2020490118. doi: 10.1073/pnas.2020490118.

Abstract

Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

Keywords: cell motility; invasion; metastasis; migration; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM12 Protein / deficiency
  • ADAM12 Protein / genetics*
  • ADAM12 Protein / metabolism*
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Heparin-binding EGF-like Growth Factor / metabolism
  • Humans
  • Hypoxia / metabolism*
  • Lung / pathology
  • Lung Neoplasms / pathology
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis / genetics
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • ADAM12 Protein
  • ADAM12 protein, human