Immunobiology of human mucin 1 in a preclinical ovarian tumor model

ABSTRACT Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the

availability of adequate preclinical models for _in vivo_ testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells,

making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express

human MUC1+/− as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-rasG12D/+) and the floxed _Pten_ gene (Pten/loxP/loxP). Injection of Cre recombinase-encoding

adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors

metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased

loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded

with a MUC1 peptide (DC1–MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the

first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies.

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Scholar  Download references ACKNOWLEDGEMENTS We would like to thank Dr Daniela Dinulescu for discussion on various aspects of the mouse model, Dr Olivera Finn for critical review of the

paper and Julia Thaller for technical assistance with histology work. This study was supported by the Department of Defense Ovarian Cancer Academy Award, Pennsylvania Department of Health,

Scaife Foundation and NIH/NCI 1 R01 CA163462-01 (to AMV). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Obstetrics, Gynecology and Reproductive Sciences, University of

Pittsburgh School of Medicine, Pittsburgh, PA, USA R A Budiu, E Elishaev, R P Edwards & A M Vlad * Magee-Women’s Research Institute, Pittsburgh, PA, USA R A Budiu, J Brozick, M Lee, R P

Edwards & A M Vlad * Department of Pathology, Magee-Women’s Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA E Elishaev * University of Pittsburgh Cancer Institute,

Pittsburgh, PA, USA P Kalinski * Department of Surgery, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, PA, USA P Kalinski * Department of Immunology,

University of Pittsburgh, Pittsburgh, PA, USA P Kalinski & A M Vlad Authors * R A Budiu View author publications You can also search for this author inPubMed Google Scholar * E Elishaev

View author publications You can also search for this author inPubMed Google Scholar * J Brozick View author publications You can also search for this author inPubMed Google Scholar * M Lee

View author publications You can also search for this author inPubMed Google Scholar * R P Edwards View author publications You can also search for this author inPubMed Google Scholar * P

Kalinski View author publications You can also search for this author inPubMed Google Scholar * A M Vlad View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to A M Vlad. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information

accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTAL TABLE 1 (DOC 12 KB) SUPPLEMENTARY FIGURE S1 (JPG 458 KB) SUPPLEMENTARY FIGURE S2 (JPG 379 KB)

SUPPLEMENTARY FIGURE S3 (JPG 328 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Budiu, R., Elishaev, E., Brozick, J. _et al._ Immunobiology of human

mucin 1 in a preclinical ovarian tumor model. _Oncogene_ 32, 3664–3675 (2013). https://doi.org/10.1038/onc.2012.397 Download citation * Received: 22 December 2011 * Accepted: 20 July 2012 *

Published: 10 September 2012 * Issue Date: 08 August 2013 * DOI: https://doi.org/10.1038/onc.2012.397 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * ovarian cancer * MUC1 * Kras * Pten * dendritic cells