Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium

• Published in: BMC cancer Vol. 20; no. 1; pp. 1020 - 9
• Main Authors: Song, Liang, Tang, Zizhi, Peng, Changsheng, Yang, Yueming, Guo, Chang, Wang, Danqing, Guo, Liandi, Chen, Jie, Liu, Cong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21-10-2020; BioMed Central; BMC
• Subjects: Animals; Biopsy; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Cell cycle; Cell Line, Tumor; Deoxyribonucleic acid; Development and progression; DNA; DNA Damage; DNA repair; Epithelial cells; Epithelium; Epithelium - drug effects; Epithelium - metabolism; Estrogens; Estrogens - toxicity; Experiments; Fallopian Tubes - drug effects; Fallopian Tubes - metabolism; Female; Gene expression; Genes; Genetic aspects; Genomes; Genomic instability; Genomics; Genotoxicity; Homologous Recombination; Hormones; Humans; Immunofluorescence; Mice; Mutation; Neoplasms, Experimental; Organ Specificity; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian surface epithelium; Ovary - drug effects; Ovary - metabolism; Phenols (Class of compounds); Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Risk factors; Steroid hormone; Steroid hormones; Surveillance equipment; Tamoxifen; Ovarian surface epithelium; Steroid hormone; DNA damage; Homologous recombination
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-020-07524-7

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.
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.
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.
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.