Introduction: We have found evidence strongly suggest that chromosomal instability (CIN) may be a contributing event in tubo-ovarian, high grade serous carcinoma (HGSC) formation. CIN is a type of genomic instability defined as a change in the rate at which gains, losses, or rearrangements of fragments of or whole chromosomes occur. We determined that CIN was present in ~95% of HGSCs and have identified that loss of one copy of the CIN gene SKP1 is associated with HGSC. SKP1 plays an important role the SKP1-CUL1-FBOX (SCF) complex, an E3 ubiquitin ligase complex that is critical for chromosome segregation and the DNA damage response. Importantly, we showed that in fallopian tube cell lines heterozygous loss of SKP1 results in CIN. My project will translate these findings to novel in vivo models biologically relevant for genetic changes in HSGC patients. Methods: To understand the contribution of CIN to HGSC etiology, I will measure the frequency of CIN in serous tubal intraepithelial carcinoma (STIC) lesions obtained from high-risk BRCA1/2 patients. CIN will be assessed using centromere enumeration probes (CEPs) and fluorescent in situ hybridization. This technique detects centromeric deviations from diploid in the target cells that is indicative of CIN. We generated Skp1^+/flox mice with an inducible cell-specific Cre driver (Pax8-Cre-ERT) to generate Skp1^+/- fallopian tube cells, and a second model to inducibly generate Skp1^+/-:Trp53^-/-. Once gene recombination is induced, mice will be aged for 1, 3 and 6 months before assessment of pathobiology and CIN in the target cells. Results: CEP analysis of STICs is ongoing. We have generated all experimental mice and have shown inducible gene recombination. Mice are aging after inducing gene recombination. Conclusions: These findings will give us a more complete understanding of CIN in HGSC in vivo, and lead to therapeutic intervention taking advantage of the CIN environment to improve patient outcomes.