1. Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis.
- Author
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Ru Wang, Godet, Ines, Yongkang Yang, Salman, Shaima, Haiquan Lu, Yajing Lyu, Qiaozhu Zuo, Yufeng Wang, Yayun Zhu, Chelsey Chen, Jianjun He, Gilkes, Daniele M., and Semenza, Gregg L.
- Subjects
METASTATIC breast cancer ,FOCAL adhesion kinase ,EPIDERMAL growth factor receptors ,BREAST cancer ,CANCER cell migration ,COMMERCIAL products - 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 lungmetastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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