High-grade serous ovarian cancer (HGSC) can be divided into four subgroups based on molecular characteristics 1,2. The proliferative or C5 subgroup is defined by MYCN pathway activation and may be associated with stem cell like behavior3. We are developing Genetically Engineered Mouse Models (GEMM) of this subtype to allow characterization of the key molecular events in the initiation of these tumours and to provide an immune competent model for testing of potential therapeutics. HGSC is believed to originate from the secretory cells of the fallopian tube, with both the tumours and the secretory cells are characterised by PAX8 expression4.
We have developed conditional GEMM that overexpress MYCN (using the TRE-MYCN-luciferase mouse) and harbour p53 pathway defects directed by the PAX8 promoter when induced with doxycycline.
Premalignant fallopian tube analysis has shown induction of MYCN mRNA and protein expression in fallopian tube secretory cells and increased expression of downstream genes in the MYCN pathway. Mice with PAX8-directed expression of oncogenes (with and without MYCN overexpression) developed enlarged kidneys, due to renal tubular adenomata, with high expression of MYCN mRNA by qRT-PCR in PAX8-TML mice. Renal tubule epithelium was also positive for MYCN protein in PAX8-TML mice. Future work will focus on detailed expression analysis of premalignant fallopian tube epithelia and the development of a tumour model utilising fallopian tube transplantation following GEMM activation.