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dc.contributor.authorHoribata, Sachi
dc.contributor.authorRogers, Katherine E.
dc.contributor.authorSadegh, David
dc.contributor.authorAnguish, Lynne J.
dc.contributor.authorMcElwee, John L.
dc.contributor.authorShah, Pragya
dc.contributor.authorThompson, Paul R
dc.contributor.authorCoonrod, Scott A.
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:02Z
dc.date.available2022-08-23T17:28:02Z
dc.date.issued2017-05-26
dc.date.submitted2017-06-06
dc.identifier.citationHoribata S, Rogers KE, Sadegh D, Anguish LJ, McElwee JL, Shah P, Thompson PR, Coonrod SA. Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration. BMC Cancer. 2017 May 26;17(1):378. doi: 10.1186/s12885-017-3354-x. PubMed PMID: 28549415; PubMed Central PMCID: PMC5446677. <a href="https://doi.org/10.1186/s12885-017-3354-x">Link to article on publisher's website</a>
dc.identifier.issn1471-2407
dc.identifier.doi10.1186/s12885-017-3354-x
dc.identifier.pmid28549415
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49994
dc.description.abstractBACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process. METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development. RESULTS: Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland. CONCLUSION: Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=28549415&dopt=Abstract">Link to article in PubMed</a>
dc.rights© The Author(s). 2017.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectPeptidylarginine deiminase 2 (PAD2)
dc.subjectTumor cell migration
dc.subjectDuctal invasion
dc.subjectMammary hyperbranching
dc.subjectBiochemistry
dc.subjectCancer Biology
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleRole of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration
dc.typeJournal Article
dc.source.journaltitleBMC cancer
dc.source.volume17
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1115&amp;context=thompson&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/113
dc.legacy.embargo2017-06-06T00:00:00-07:00
dc.identifier.contextkey10256969
refterms.dateFOA2022-08-23T17:28:02Z
html.description.abstract<p>BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.</p> <p>METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development.</p> <p>RESULTS: Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland.</p> <p>CONCLUSION: Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.</p>
dc.identifier.submissionpaththompson/113
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages378


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