Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
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RESEARCH ARTICLE
Open Access
Cell type-specific genotoxicity in estrogenexposed ovarian and fallopian epithelium Liang Song1†, Zizhi Tang1†, Changsheng Peng1†, Yueming Yang1, Chang Guo1, Danqing Wang1, Liandi Guo2*, Jie Chen1* and Cong Liu1*
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. Keywords: Ovarian surface epithelium, Steroid hormone, DNA damage, Homologous recombination
Background Cancer genomes accumulate mutations upon loss of genome stability. During carcinogenesis and progression of cancer, cells are challenged by various genotoxic insults, which pose threats to genomic stability [1, 2]. Encounter of DNA lesions requires efficient DNA damage responses (DDR) to * Correspondence: [email protected]; [email protected]; [email protected] † Liang Song, Zizhi Tang and Changsheng Peng contributed equally to this work. 2 College of Pharmacy, Southwest Minzu University, Chengdu 610041, People’s Republic of China 1 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, Chengdu 610041, People’s Republic of China
prevents loss and gain of genetic information. DNA lesions can be quickly monitored by ATM (Ataxia-Telangiectasia mutated) and ATR (A-T-related)-mediated cell cycle checkpoint [3], followed by actions of repair factors such as RAD51, BRCA1 and 53BP1 to eliminate DNA
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