Human cervical cancer is a leading cause of death by cancer among women worldwide. It is caused by a subset of anogenital Human papillomaviruses (HPVs). The genomes of these high risk HPVs are found present in virtually all human cervical cancers and a subset of viral genes, E6 and E7 commonly expressed. E6 and E7 possess transforming and tumorigenic properties leading to their definition as oncogenes. Cervical cancer arises over a period of decades following initial exposure to these high risk HPVs, and a number of cofactors have been identified including reproductive hormones. In a prior study using a transgenic mouse model for HPV-associated cervical cancer we determined that, in addition to these two viral oncogenes, estrogen contributes not only to the genesis of cervical cancer but also its maintenance and continued growth. In this grant application we propose experiments to evaluate the role of estrogen receptor (ER)-dependent versus ER-independent mechanisms of estrogen-mediated carcinogenesis in this mouse model for human cervical cancer. We also propose experiments to assess the efficacy of anti-estrogenic drugs in preventing and treating cervical cancer. These preclinical studies should determine whether estrogen and its receptors are valid targets in preventing and treating human cervical cancer.
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