Requirement for Stromal Estrogen Receptor Alpha in Cervical Neoplasia

The major etiological factor for cervical cancer is the high-risk human papillomavirus (HPV), which encodes E6 and E7 oncogenes. However, HPV is not sufficient, and estrogen has been proposed as an etiological cofactor for the disease. Its requirement has been demonstrated in mouse models for HPV-associated cervical cancer (e.g., K14E7 transgenic mice). Although germline knockout of estrogen receptor alpha (ER alpha) renders mice resistant to cervical cancer, the cell-type-specific requirement for ER alpha is not known. In this study, we demonstrate that temporal deletion of stromal ER alpha induced complete regression of cervical dysplasia in K14E7 mice. Our results strongly support the hypothesis that stromal ER alpha is necessary for HPV-induced cervical carcinogenesis and implicate paracrine mechanisms involving ER alpha signaling in the development of estrogen-dependent cervical cancers. This is the first evidence to support the importance of stromal ER alpha in estrogen-dependent neoplastic disease of the female reproductive tract.