Estrogen induces genomic instability in high-risk HPV-infected cervix and promotes the carcinogenesis of cervical adenocarcinoma

High-risk human papillomavirus (HPV) infection is the major cause of cervical cancer. However, the factors that modulate the process from infection to carcinogenesis are poorly understood. Although cervical cancer is clinically considered an estrogen-independent tumor, the role of estrogen in cervical cancer, particularly cervical adenocarcinoma, remains controversial. In this study, we showed that estrogen/GPR30 signaling induced genomic instability, which leads to carcinogenesis in high-risk HPV-infected endocervical columnar cell lines. The expression of estrogen receptors in a normal cervix was confirmed through immunohistochemical analysis which showed that G protein-coupled receptor 30 (GPR30) was predominantly expressed in endocervical glands and estrogen receptor-α (ERα) was expressed at higher levels in the squamous epithelium than in the cervical gland. E2 increased the proliferation of cervical cell lines, particularly normal endocervical columnar and adenocarcinoma cells via GPR30 rather than ERα, and increased the accumulation of DNA double-strand breaks (DSBs) in high-risk HPV-E6-expressing cells. The increase in DSBs was caused by the impairment of Rad 51 and accumulation of topoisomerase-2-DNA complexes under HPV-E6 expression. In addition, chromosomal aberrations increased in cells with E2-induced DSB accumulation. Collectively, we conclude that E2 exposure in high-risk HPV-infected cervical cells increases DSBs, leading to genomic instability and thus carcinogenesis via GPR30.