Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 19, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2020490118
Keywords
tumor microenvironment; cell motility; migration; invasion |; metastasis
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Funding
- American Cancer Society
- Armstrong Family Foundation
- Cindy Rosencrans Fund for TripleNegative Breast Cancer
- China Scholarship Council
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This study discovered that HIFs induce the expression of ADAM12, leading to EGFR signaling activation and subsequently promoting breast cancer cell migration, invasion, and metastasis. Inhibition of ADAM12 expression or activity can effectively reduce tumor cell migration, invasion, and lung metastasis.
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.
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