Modelo animal geneticamente modificado de carcinoma de células escamosas de vulva com deleção do gene ARID1A e ativação do oncogene Kras

Abstract

Gynecological cancer remains a significant public health issue. In 2017, over 100,000 women will be diagnosed with a gynecologic cancer and more than 31,000 will die in the United States. Primary vulvar cancer accounts for less than 5% of gynecological cancers diagnosed, but the curative surgical treatment for deeply invasive tumors has considerable morbidity. Since vulvar cancer is an infrequent tumor, randomized trials of therapeutic approaches in women are uncommon. Thus, model systems are needed to understand the pathophysiology of the disease to develop improved therapies. To study female reproductive tract cancers, in particular endometrial cancer, we created a genetically engineered mouse model using the progesterone receptor-Cre (PgrCre), which conditionally deletes in the uterus. When we deleted Arid1a, the proposed tumor suppressor that is thought to be a driver mutation in endometrial cancer, the female mice were infertile but did not develop endometrial cancer. Thus, we added oncogenic Kras (KrasG12D). Surprisingly, these female mice (PgrCreArid1af/fKrasSLS-G12D) developed large vulvar tumors, with 100% penetrance by 8 weeks of life. Sections of fixed tissue from vulva, vagina, cervix, uterus and ovaries of the mice were submitted to histological and immunohistochemistry studies to evaluate the KrasG12D mutation, Arid1a deletion and other biomarkers to characterize the pathways of oncogenesis in vulvar squamous cell carcinoma. Histological examination of uterine and ovarian tissues revealed normal structures without malignancy or benign tumors. This mouse model may allow a better understanding of the molecular mechanisms underlying the genetic transformation of vulvar cancer and can be used to develop targets for therapy.