No abstract

Recent sequencing studies showed that loss-of-function mutations in ARID1A (AT-rich interactive domain 1a) were enriched in gynecologic malignancies. However, multiple mouse models with deletion of Arid1a did not exhibit gynecologic malignancy. Oncogenic KRAS mutations are a common finding in endometrial cancers. However, expression of oncogenic Kras (KrasG12D) in the uterus was not sufficient to develop endometrial cancer. These results suggest that both ARID1A deletion and oncogenic KRAS require additional hits before driving gynecologic malignancy. To determine the role of the combination effects of deletion of Arid1a and oncogenic Kras, Arid1aflox/flox mice were crossed to KrasLox-Stop-Lox-G12D/+ mice using progesterone receptor Cre (PgrCre/+). Survival studies, histology, and immunohistochemistry were used to characterize the phenotype. Hormone dependence was evaluated by ovarian hormone depletion and estradiol replacement. Arid1aflox/flox; KrasLox-Stop-Lox-G12D/+; PgrCre/+ (AKP) mice exhibited early euthanasia due to large vaginal tumors, which were invasive squamous cell carcinoma. Younger mice exhibited precancerous intraepithelial lesions that progressed to invasive squamous cell carcinoma with age. Immunohistochemistry supported the pathological diagnosis with abnormal expression and localization of cytokeratin 5, tumor protein P63, cyclin dependent kinase inhibitor 2A (CDKN2A or p16), and marker of proliferation Ki-67. Vaginal lesions in AKP mice were hormone dependent. Ovarian hormone deletion in AKP mice resulted in atrophic vaginal epithelium without evidence of vaginal tumors. Estradiol replacement in ovarian hormone depleted AKP mice resulted in lesions that resembled the squamous cell carcinoma in intact mice. AKP mice did not develop endometrial cancer. Arid1a deletion with KrasG12D expression drives invasive vaginal squamous cell carcinoma. This mouse can be used to study the transition from benign precursor lesions into invasive vaginal squamous cell carcinoma offering insights into progression.