@article{2defc64639134fda8e72b3bb069ac3b0,
title = "Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis",
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.",
keywords = "Cell motility, Invasion, Metastasis, Migration, Tumor microenvironment",
author = "Ru Wang and Ines Godet and Yongkang Yang and Shaima Salman and Haiquan Lu and Yajing Lyu and Qiaozhu Zuo and Yufeng Wang and Yayun Zhu and Chelsey Chen and Jianjun He and Gilkes, {Daniele M.} and Semenza, {Gregg L.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Weibo Luo (University of Texas South-western Medical Center, Dallas) for generously providing CRISPR knockout subclones of MDA-MB-231 cells; Samantha Garcia and Rachel Geisler (Novus Biologicals) for generously providing antibodies against HIF-1α, HIF-2α, HIF-1β, phospho-EGFR, and HB-EGF; and Byung Hyun Yi for assistance with cell motility measurements. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. This work was supported by grants from the American Cancer Society, Armstrong Family Foundation, and the Cindy Rose-ncrans Fund for Triple-Negative Breast Cancer (to G.L.S.), and the China Scholarship Council (to R.W.). Funding Information: We thank Dr. Weibo Luo (University of Texas Southwestern Medical Center, Dallas) for generously providing CRISPR knockout subclones of MDA-MB-231 cells; Samantha Garcia and Rachel Geisler (Novus Biologicals) for generously providing antibodies against HIF-1?, HIF-2?, HIF-1?, phospho-EGFR, and HB-EGF; and Byung Hyun Yi for assistance with cell motility measurements. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. This work was supported by grants from the American Cancer Society, Armstrong Family Foundation, and the Cindy Rosencrans Fund for Triple-Negative Breast Cancer (to G.L.S.), and the China Scholarship Council (to R.W.). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = may,
day = "11",
doi = "10.1073/pnas.2020490118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "19",
}