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

Cheryl A. Sherman-Baust, Elisabetta Kuhn, Blanca L. Valle, Ie Ming Shih, Robert J Kurman, Tian-Li Wang, Tomokazu Amano, Minoru Sh Ko, Ichiro Miyoshi, Yoshihiko Araki, Elin Lehrmann, Yongqing Zhang, Kevin G. Becker, Patrice J. Morin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)228-237
Number of pages10
JournalJournal of Pathology
Volume233
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Fallopian Tubes
Ovarian Neoplasms
Carcinoma
Viral Tumor Antigens
Epithelium
Ovary
Polyomavirus Transforming Antigens
Type II DNA Topoisomerase
Public Sector
Carcinoma in Situ
Microarray Analysis
Transgenic Mice
Genes
Adenocarcinoma
Immunohistochemistry

Keywords

  • fallopian tube
  • intraepithelial carcinoma
  • ovarian cancer
  • p53
  • Top2a
  • transgenic mouse model

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development. / Sherman-Baust, Cheryl A.; Kuhn, Elisabetta; Valle, Blanca L.; Shih, Ie Ming; Kurman, Robert J; Wang, Tian-Li; Amano, Tomokazu; Ko, Minoru Sh; Miyoshi, Ichiro; Araki, Yoshihiko; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.; Morin, Patrice J.

In: Journal of Pathology, Vol. 233, No. 3, 2014, p. 228-237.

Research output: Contribution to journalArticle

Sherman-Baust, CA, Kuhn, E, Valle, BL, Shih, IM, Kurman, RJ, Wang, T-L, Amano, T, Ko, MS, Miyoshi, I, Araki, Y, Lehrmann, E, Zhang, Y, Becker, KG & Morin, PJ 2014, 'A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development', Journal of Pathology, vol. 233, no. 3, pp. 228-237. https://doi.org/10.1002/path.4353
Sherman-Baust, Cheryl A. ; Kuhn, Elisabetta ; Valle, Blanca L. ; Shih, Ie Ming ; Kurman, Robert J ; Wang, Tian-Li ; Amano, Tomokazu ; Ko, Minoru Sh ; Miyoshi, Ichiro ; Araki, Yoshihiko ; Lehrmann, Elin ; Zhang, Yongqing ; Becker, Kevin G. ; Morin, Patrice J. / A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development. In: Journal of Pathology. 2014 ; Vol. 233, No. 3. pp. 228-237.
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