Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo

摘要: Ovarian cancer is a complex and deadly disease that remains difficult to detect at an early curable stage. Furthermore, although some oncogenic (Kras, Pten/PI3K Trp53) pathways are frequently mutated, deleted or amplified in ovarian known, how these initiate drive specific morphological phenotypes tumor outcomes remain unclear. We recently generated Ptenfl/fl; KrasG12D; Amhr2-Cre mice disrupt the Pten gene express stable mutant form of KrasG12D surface epithelial (OSE) cells. On basis histopathologic criteria, developed low-grade serous papillary adenocarcinomas age with 100% penetrance. This highly reproducible phenotype provides first mouse model which study this subtype. OSE cells isolated from ovaries 5 10 weeks exhibit temporal changes expression Mullerian marker genes, grow soft agar develop ectopic invasive tumors recipient mice, indicating transformed. Gene profiling identified mRNAs microRNAs differentially expressed purified derived compared wild-type Mapping transcripts genes between data sets, Kras signature human cell lines array documented significant overlap, KRAS key driver transformation context. Two hallmarks elevated tumor-suppressor Trp53 (p53) its microRNA target, miR-34a-c. propose TRP53 miR-34a-c may exert negatively regulatory effects reduce proliferative potential leading adenocarcinoma phenotype.