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A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high‐grade serous carcinoma development
Author(s) -
ShermanBaust Cheryl A,
Kuhn Elisabetta,
Valle Blanca L,
Shih IeMing,
Kurman Robert J,
Wang TianLi,
Amano Tomokazu,
Ko Minoru SH,
Miyoshi Ichiro,
Araki Yoshihiko,
Lehrmann Elin,
Zhang Yongqing,
Becker Kevin G,
Morin Patrice J
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4353
Subject(s) - serous carcinoma , fallopian tube , serous fluid , biology , ovarian cancer , pathology , neoplastic transformation , ovarian carcinoma , epithelium , malignant transformation , immunohistochemistry , cancer research , cancer , medicine , immunology , carcinogenesis , anatomy , genetics
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 II α , 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.