A chimeric mouse model of ovarian cancer driven by inducible expression of PI3K catalytic subunit (p110α) Free

3869

Ovarian cancer is one of the most deadly diseases among women. The unmet medical need is very high due to the lack of treatment options. One key feature of ovarian cancer is the frequent alteration of genes involved in PI3 kinase signaling. The tumor suppressor PTEN is frequently mutated or lost and conversely, activating mutations have been identified in p110α, the catalytic subunit of PI3K. It has been shown that knock out of PTEN in conjunction with KRAS activation resulted in adenocarcinomas derived from the ovary surface epithelium. It is not clear, however, whether activation of p110α is equally sufficient for tumorigenesis. To address that question, we made a complex inducible ovary tumor model using our unique chimeric model technology. This model features homozygous knock out of the Ink4a/Arf tumor suppressor gene, ovary specific expression of rtTA and luciferase driven by AMHRII promoter, and doxycycline inducible expression of myristylated p110α. The chimeric mice developed tumors with a latency of 4-7 months. Histo-pathological analysis revealed two types of malignant cells, endometrioid adenocarcinomas and tumors originated from granulosa cells. Immunohistochemistry confirmed the expression of p110 in these tumor cells. These tumors are suitable for propagation and potential pathway relevant drug studies.