title: A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
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.
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Sherman-Baust
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Kuhn
authors.forename: Blanca L
authors.initials: BL
authors.lastname: Valle
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Amano
authors.forename: Minoru S H
authors.initials: MS
authors.lastname: Ko
authors.forename: Ichiro
authors.initials: I
authors.lastname: Miyoshi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Araki
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Patrice J
authors.initials: PJ
authors.lastname: Morin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005187:Fallopian Tubes / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006023:Glycoproteins; C097024:Ovgp1 protein, mouse; D000075223:Poly-ADP-Ribose Binding Proteins; D016159:Tumor Suppressor Protein p53; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse
keywords: Top2a; fallopian tube; intraepithelial carcinoma; ovarian cancer; p53; transgenic mouse model