Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and 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 elu...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (19), p.1-12 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Wang, Ru Godet, Ines Yang, Yongkang Salman, Shaima Lu, Haiquan Lyu, Yajing Zuo, Qiaozhu Wang, Yufeng Zhu, Yayun Chen, Chelsey He, Jianjun Gilkes, Daniele M. Semenza, Gregg L. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.2020490118 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2020490118</identifier><identifier>PMID: 33952697</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Breast cancer ; Cell migration ; Epidermal growth factor ; Epidermal growth factor receptors ; Focal adhesion kinase ; Growth factors ; Heparin ; Hypoxia ; Hypoxia-inducible factors ; Immunodeficiency ; Kinases ; Metalloproteinase ; Metastases ; Metastasis ; Phosphorylation</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-05, Vol.118 (19), p.1-12</ispartof><rights>Copyright National Academy of Sciences May 11, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-56c53e3e064f83d8a62229a344f77e45297c4a193b4848d79702a7bdbbf8f7a03</citedby><cites>FETCH-LOGICAL-c443t-56c53e3e064f83d8a62229a344f77e45297c4a193b4848d79702a7bdbbf8f7a03</cites><orcidid>0000-0002-2768-1753 ; 0000-0002-4889-5144 ; 0000-0002-3382-7181 ; 0000-0003-3984-9338</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27040511$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27040511$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33952697$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Ru</creatorcontrib><creatorcontrib>Godet, Ines</creatorcontrib><creatorcontrib>Yang, Yongkang</creatorcontrib><creatorcontrib>Salman, Shaima</creatorcontrib><creatorcontrib>Lu, Haiquan</creatorcontrib><creatorcontrib>Lyu, Yajing</creatorcontrib><creatorcontrib>Zuo, Qiaozhu</creatorcontrib><creatorcontrib>Wang, Yufeng</creatorcontrib><creatorcontrib>Zhu, Yayun</creatorcontrib><creatorcontrib>Chen, Chelsey</creatorcontrib><creatorcontrib>He, Jianjun</creatorcontrib><creatorcontrib>Gilkes, Daniele M.</creatorcontrib><creatorcontrib>Semenza, Gregg L.</creatorcontrib><title>Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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. 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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.</description><subject>Biological Sciences</subject><subject>Breast cancer</subject><subject>Cell migration</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Focal adhesion kinase</subject><subject>Growth factors</subject><subject>Heparin</subject><subject>Hypoxia</subject><subject>Hypoxia-inducible factors</subject><subject>Immunodeficiency</subject><subject>Kinases</subject><subject>Metalloproteinase</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Phosphorylation</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdkc1v1DAQxS1ERZfCmRMoEhcuaf0Z2xekVYG2UhEXOFsTZwJeZZ1gJ1X73-Nl26XlZI3ez09v5hHyhtFTRrU4myLkU045lZYyZp6RFaOW1U0Zn5MVpVzXRnJ5TF7mvKGUWmXoC3IshFW8sXpF_OXdNN4GqEPsFh_aAase_DymusMJY4dxrtaf1l8Zr_B2SphzGGO1xS7AjLlqE0KeKw_RY6pCvIG_OsSuMHORypxfkaMehoyv798T8uPL5-_nl_X1t4ur8_V17aUUc60arwQKpI3sjegMNJxzC0LKXmuUilvtJTArWmmk6bTVlINuu7btTa-BihPyce87LW1J6Ev2BIObUthCunMjBPdUieGX-zneOMN4o40tBh_uDdL4e8E8u23IHocBIo5Ldlxx3pRrK13Q9_-hm3FJsay3oxpbLq9Moc72lE9jzgn7QxhG3a5AtyvQ_Suw_Hj3eIcD_9BYAd7ugU0uLR10rqmkijHxB1AioZ8</recordid><startdate>20210511</startdate><enddate>20210511</enddate><creator>Wang, Ru</creator><creator>Godet, Ines</creator><creator>Yang, Yongkang</creator><creator>Salman, Shaima</creator><creator>Lu, Haiquan</creator><creator>Lyu, Yajing</creator><creator>Zuo, Qiaozhu</creator><creator>Wang, Yufeng</creator><creator>Zhu, Yayun</creator><creator>Chen, Chelsey</creator><creator>He, Jianjun</creator><creator>Gilkes, Daniele M.</creator><creator>Semenza, Gregg L.</creator><general>National Academy of Sciences</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2768-1753</orcidid><orcidid>https://orcid.org/0000-0002-4889-5144</orcidid><orcidid>https://orcid.org/0000-0002-3382-7181</orcidid><orcidid>https://orcid.org/0000-0003-3984-9338</orcidid></search><sort><creationdate>20210511</creationdate><title>Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis</title><author>Wang, Ru ; 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| subjects | Biological Sciences Breast cancer Cell migration Epidermal growth factor Epidermal growth factor receptors Focal adhesion kinase Growth factors Heparin Hypoxia Hypoxia-inducible factors Immunodeficiency Kinases Metalloproteinase Metastases Metastasis Phosphorylation |
| title | Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis |
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