Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis [Medical Sciences],Proceedings of the National Academy of Sciences of the United States of America

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Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2020490118
Ru Wang _{1,

2,

3} , Ines Godet ₄ , Yongkang Yang _{2,

3} , Shaima Salman _{2,

3} , Haiquan Lu _{2,

3} , Yajing Lyu _{2,

3} , Qiaozhu Zuo _{2,

3} , Yufeng Wang _{2,

3} , Yayun Zhu _{2,

3} , Chelsey Chen _{2,

3} , Jianjun He ₁ , Daniele M Gilkes ₄ , Gregg L Semenza _{3,

4,

5,

6,

7,

8,

9}

Affiliation

Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

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.

中文翻译：

缺氧诱导因子依赖性 ADAM12 表达介导乳腺癌侵袭和转移 [医学科学]

在原发肿瘤活检中缺氧诱导因子 (HIF) 表达增加的乳腺癌患者发生转移的风险增加，这是乳腺癌相关死亡的主要原因。瘤内缺氧和 HIFs 调节转移的机制尚未完全阐明。在本文中，我们报告人类乳腺癌细胞暴露于缺氧会激活表皮生长因子受体 (EGFR) 信号，该信号由 HIF 依赖性表达的解整合素和金属蛋白酶 12 (ADAM12) 介导，后者介导肝素的胞外域脱落增加-结合 EGF 样生长因子，一种 EGFR 配体，导致粘着斑激酶的 EGFR 依赖性磷酸化。抑制 ADAM12 表达或活性降低了体外缺氧诱导的乳腺癌细胞迁移和侵袭，

更新日期：2021-05-06

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