Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
Liang Song,
Zizhi Tang,
Changsheng Peng,
Yueming Yang,
Chang Guo,
Danqing Wang,
Liandi Guo,
Jie Chen,
Cong Liu
Affiliations
Liang Song
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Zizhi Tang
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Changsheng Peng
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Yueming Yang
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Chang Guo
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Danqing Wang
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Liandi Guo
College of Pharmacy, Southwest Minzu University
Jie Chen
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Cong Liu
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University
Abstract Background Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particularly susceptible to the malfunction of genome surveillance system. Methods To explore the genotoxic responses in the unique context of microenvironment for ovarian epithelium that is periodically exposed to high-level steroid hormones, we examined estrogen-induced DNA damage by immunofluorescence in OvCa cell lines, animal and human samples. Results We found that OvCa cells are burdened with high levels of endogenous DNA damage that is not correlated with genomic replication. The elevation of damage burden is attributable to the excessive concentration of bioactive estrogen instead of its chemomimetic derivative (tamoxifen). Induction of DNA lesions by estrogen is dependent on the expression of hormone receptors, and occurs in G1 and non-G1 phases of cell cycle. Moreover, depletion of homologous recombination (HR) genes (BRCA1 and BRCA2) exacerbated the genotoxicity of estrogen, highlighting the role of HR to counteract hormone-induced genome instability. Finally, the estrogen-induced DNA damage was reproduced in the epithelial compartments of both ovarian and fallopian tubes. Conclusions Taken together, our study disclose that estrogen-induced genotoxicity and HR deficiency perturb the genome stability of ovarian and fallopian epithelial cells, representing microenvironmental and genetic risk factors, respectively.
