Abstract 2684: Modeling a prototypical type I ovarian carcinoma in the mouse based on oviductal versus ovarian epithelial transformation: which is superior
Authors: Wu Rong , Zhai Yali , Kuick Rork , Garcia Paloma , Naseem Anum , Fearon Eric R. , Cho kathleen R. 
Published: July 2016

Abstract
Type I ovarian carcinomas are relatively indolent tumors that are nonetheless deadly if detected too late. Endometrioid carcinoma (EC) is a prototypical Type I ovarian cancer subtype. Existing mouse models of the disease based on transformation of the ovarian surface epithelium (OSE) take advantage of known EC genetic signatures but fail to capture fully the clinical disease progression and tumor phenotype. We previously described a mouse ovarian EC model in which the Apc and Pten tumor suppressor genes are conditionally deleted in the OSE via bursal injection of adenovirus expressing Cre recombinase (AdCre). We now report a new mouse model of EC in which the Ovgp1 (oviductal glycoprotein) promoter regulates expression of tamoxifen-inducible Cre recombinase specifically in the mouse oviductal epithelium (equivalent to human fallopian tube epithelium [FTE]), and not in the OSE or endometrium. Ovgp1-iCreERT2;Apcfl/fl;Ptenfl/fl mice treated with tamoxifen (TAM) develop oviductal tumors over months rather than weeks. The oviductal EC morphology closely resembles that of human ovarian ECs, with overt gland formation throughout, whereas ovarian bursal injection of AdCre in Ovgp1-iCreERT2;Apcfl/fl;Ptenfl/fl mice results in OSE-derived ECs that are poorly differentiated and include a prominent spindle cell component, consistent with our prior work. OSE-derived tumors progress rapidly, with none of the mice surviving beyond 14 weeks post-AdCre injection. Littermates with FTE-derived tumors survive much longer (&gt;30 weeks post TAM). The slow progression and late (typically &gt;16 weeks post TAM) metastasis to ovary and omentum associated with the FTE-derived tumors are more akin to the relatively indolent behavior characteristic of Type I ovarian carcinoma in humans. To further evaluate which of the two types of mouse tumors more closely resemble human ovarian tumors, we profiled gene expression in 6 FTE- and 5 OSE-derived Apc/Pten-deficient tumors, and compared the groups to each other and to data from 99 human ovarian carcinomas we analyzed previously (including 37 endometrioid, 41 serous, and 13 clear cell, and 8 mucinous carcinomas). Based on gene expression, the FTE-derived tumors are more correlated to every class of human ovarian tumors (p &lt; 2 X10−6 in all 4 comparisons), with highest correlation to human ECs (particularly those with mutant CTNNB1) and mucinous carcinomas. This new model of EC, based on transformation of Mullerian epithelium rather than the OSE, will likely prove more suitable for translational applications, including pre-clinical testing of novel therapeutics for ovarian EC.
Citation Format: Rong Wu, Yali Zhai, Rork Kuick, Paloma Garcia, Anum Naseem, Eric R. Fearon, kathleen R. Cho. Modeling a prototypical type I ovarian carcinoma in the mouse based on oviductal versus ovarian epithelial transformation: which is superior. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2684.