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dc.contributor.authorMcElwee, John L.
dc.contributor.authorMohanan, Sunish
dc.contributor.authorGriffith, Obi L.
dc.contributor.authorBreuer, Heike C.
dc.contributor.authorAnguish, Lynne J.
dc.contributor.authorCherrington, Brian D.
dc.contributor.authorPalmer, Ashley M.
dc.contributor.authorHowe, Louise R.
dc.contributor.authorSubramanian, Venkataraman
dc.contributor.authorCausey, Corey P.
dc.contributor.authorThompson, Paul R
dc.contributor.authorGray, Joe W.
dc.contributor.authorCoonrod, Scott A.
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:10Z
dc.date.available2022-08-23T17:28:10Z
dc.date.issued2012-10-30
dc.date.submitted2015-05-22
dc.identifier.citationBMC Cancer. 2012 Oct 30;12:500. doi: 10.1186/1471-2407-12-500. <a href="http://dx.doi.org/10.1186/1471-2407-12-500">Link to article on publisher's site</a>
dc.identifier.issn1471-2407 (Linking)
dc.identifier.doi10.1186/1471-2407-12-500
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50020
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractBACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects. METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes. RESULTS: We show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 x 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67. CONCLUSION: Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23110523&dopt=Abstract">Link to Article in PubMed</a>
dc.rights© 2012 McElwee et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<a href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</a>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectBreast Neoplasms
dc.subjectCell Line, Tumor
dc.subjectDisease Models, Animal
dc.subjectDisease Progression
dc.subjectEnzyme Inhibitors
dc.subjectFemale
dc.subjectGene Expression Profiling
dc.subjectHumans
dc.subjectHydrolases
dc.subjectMice
dc.subjectMice, Nude
dc.subjectNeoplasm Proteins
dc.subjectTumor Markers, Biological
dc.subjectBiochemistry
dc.subjectCancer Biology
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleIdentification of PADI2 as a potential breast cancer biomarker and therapeutic target.
dc.typeJournal Article
dc.source.journaltitleBMC cancer
dc.source.volume12
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1029&amp;context=thompson&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/30
dc.identifier.contextkey7135691
refterms.dateFOA2022-08-23T17:28:10Z
html.description.abstract<p>BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.</p> <p>METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes.</p> <p>RESULTS: We show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 x 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67.</p> <p>CONCLUSION: Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.</p>
dc.identifier.submissionpaththompson/30
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages500


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