Abstract B76: Oncogenic Kras and Pik3ca can cooperate with inactivation of various tumor suppressor genes to generate high-grade serous carcinomas in the mouse oviduct
Authors: Zhai Yali , Schulman Stephanie , Khandwala Neil , Fearon Eric R. , Cho Kathleen R. 
Published: August 2018

Recent studies suggest that most “ovarian” high-grade serous carcinomas (HGSCs) actually originate from precursors in the fallopian tubal epithelium (FTE) known as serous tubal intraepithelial carcinomas (STICs). We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen-regulated Cre recombinase in the oviductal epithelium—equivalent to human FTE. We recently employed Ovgp1-iCreERT2 mice to show that FTE-specific inactivation of several different combinations of tumor suppressor genes (TSGs) that are recurrently mutated in human HGSCs—namely Brca1, Trp53, Rb1, and Nf1---results in STICs that progress to HGSC or Müllerian carcinosarcoma over several months, and to widely metastatic disease in a subset of mice. The histopathologic features of the mouse tumors closely resemble those of their human tumor counterparts.

The PI3K and RAS signaling pathways are frequently dysregulated in human HGSCs, often via amplification (and much less frequently mutation) of PIK3CA and KRAS, respectively. We wished to determine if mutant Kras or Pik3ca can cooperate with inactivation of various combinations of the aforementioned TSGs to generate oviductal HGSCs in the mouse, and were particularly interested in generating tumors in the context of intact Brca1/2. We found that conditional mutation of Kras (G12D) can cooperate with Brca1, Trp53, Rb1, and/or Nf1 inactivation in the generation of HGSCs in the mouse. Only two TSGs alterations (Trp53 and Rb1) were required for tumor development in the context of mutant Kras. HGSCs and/or carcinosarcomas developed rapidly in the context of mutant Kras and bi-allelic inactivation of Trp53 and Rb1, even when Brca1 and Brca2 were intact. HGSC and/or carcinosarcoma also developed in the oviducts following conditional mutation of Pik3ca (E545K) and various combinations of inactivated Brca1, Trp53, Rb1, and/or Nf1 alleles. When compared to our prior study of mouse tumors arising in the context of TSG inactivation alone, our data show that that 1) oncogenic Kras or Pik3ca accelerates tumor development and progression in mice carrying floxed Brca1, Trp53, Rb1, and/or Nf1 alleles compared to mice with the same TSG defects but without mutant Kras or Pik3ca; 2) oviductal tumorigenesis in the mouse requires fewer TSGs defects when mutant Kras or Pik3ca is also present; and 3) oviductal HGSCs can arise in the context of wild-type Brca1/2. Collectively, these models recapitulate the heterogeneity of human HGSC and should prove useful for testing new approaches for prevention, early detection, and treatment.

Citation Format: Yali Zhai, Stephanie Schulman, Neil Khandwala, Eric R. Fearon, Kathleen R. Cho. Oncogenic Kras and Pik3ca can cooperate with inactivation of various tumor suppressor genes to generate high-grade serous carcinomas in the mouse oviduct. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B76.