Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration
Authors
Horibata, SachiRogers, Katherine E.
Sadegh, David
Anguish, Lynne J.
McElwee, John L.
Shah, Pragya
Thompson, Paul R
Coonrod, Scott A.
Document Type
Journal ArticlePublication Date
2017-05-26Keywords
Peptidylarginine deiminase 2 (PAD2)Tumor cell migration
Ductal invasion
Mammary hyperbranching
Biochemistry
Cancer Biology
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
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. 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.Source
Horibata 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. Link to article on publisher's websiteDOI
10.1186/s12885-017-3354-xPermanent Link to this Item
http://hdl.handle.net/20.500.14038/49994PubMed ID
28549415Related Resources
Link to article in PubMedRights
© The Author(s). 2017.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1186/s12885-017-3354-x