Volume 233, Issue 3 p. 228-237
Original Paper

A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development

Cheryl A Sherman-Baust

Cheryl A Sherman-Baust

Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, USA

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Elisabetta Kuhn

Elisabetta Kuhn

Department of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Blanca L Valle

Blanca L Valle

Dept of Otolaryngology Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Ie-Ming Shih

Ie-Ming Shih

Department of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Robert J Kurman

Robert J Kurman

Department of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Tian-Li Wang

Tian-Li Wang

Department of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Tomokazu Amano

Tomokazu Amano

Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

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Minoru SH Ko

Minoru SH Ko

Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

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Ichiro Miyoshi

Ichiro Miyoshi

Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Sciences, Japan

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Yoshihiko Araki

Yoshihiko Araki

Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Urayasu City, Chiba, Japan

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Elin Lehrmann

Elin Lehrmann

Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

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Yongqing Zhang

Yongqing Zhang

Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

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Kevin G Becker

Kevin G Becker

Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

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Patrice J Morin

Corresponding Author

Patrice J Morin

Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, USA

Department of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence to: PJ Morin, American Association for Cancer Research, 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106, USA. E-mail: [email protected]Search for more papers by this author
First published: 20 March 2014
Citations: 97
No conflicts of interest were declared.

Abstract

Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp–TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp–TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to ‘p53 signatures’ in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp–TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease. Published 2014. This article has been contributed to by US Government employees and their work is in the public domain in the USA.