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

Ru Wang, Ines Godet, Yongkang Yang, Shaima Salman, Haiquan Lu, Yajing Lyu, Qiaozhu Zuo, Yufeng Wang, Yayun Zhu, Chelsey Chen, Jianjun He, Daniele M. Gilkes, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review


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 lungmetastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

Original languageEnglish (US)
Article numbere2020490118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - May 11 2021


  • Cell motility
  • Invasion
  • Metastasis
  • Migration
  • Tumor microenvironment

ASJC Scopus subject areas

  • General


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