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    Identification of PADI2 as a potential breast cancer biomarker and therapeutic target.

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    1471_2407_12_500.pdf
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    Authors
    McElwee, John L.
    Mohanan, Sunish
    Griffith, Obi L.
    Breuer, Heike C.
    Anguish, Lynne J.
    Cherrington, Brian D.
    Palmer, Ashley M.
    Howe, Louise R.
    Subramanian, Venkataraman
    Causey, Corey P.
    Thompson, Paul R
    Gray, Joe W.
    Coonrod, Scott A.
    Show allShow less
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2012-10-30
    Keywords
    Animals
    Antineoplastic Agents
    Breast Neoplasms
    Cell Line, Tumor
    Disease Models, Animal
    Disease Progression
    Enzyme Inhibitors
    Female
    Gene Expression Profiling
    Humans
    Hydrolases
    Mice
    Mice, Nude
    Neoplasm Proteins
    Tumor Markers, Biological
    Biochemistry
    Cancer Biology
    Enzymes and Coenzymes
    Medicinal-Pharmaceutical Chemistry
    Therapeutics
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    Abstract
    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. 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.
    Source
    BMC Cancer. 2012 Oct 30;12:500. doi: 10.1186/1471-2407-12-500. Link to article on publisher's site
    DOI
    10.1186/1471-2407-12-500
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/50020
    Notes

    At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

    Related Resources
    Link to Article in PubMed
    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 (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    ae974a485f413a2113503eed53cd6c53
    10.1186/1471-2407-12-500
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