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

Autor: Changsheng Peng, Chang Guo, Cong Liu, Yueming Yang, Danqing Wang, Liandi Guo, Jie Chen, Zizhi Tang, Liang Song
Rok vydání: 2020
Předmět:
0301 basic medicine
Genome instability
Cancer Research
Steroid hormone
endocrine system diseases
medicine.drug_class
DNA repair
DNA damage
Biology
medicine.disease_cause
lcsh:RC254-282
Epithelium
03 medical and health sciences
Mice
0302 clinical medicine
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Homologous recombination
Gene
Fallopian Tubes
BRCA2 Protein
Ovarian Neoplasms
BRCA1 Protein
Ovary
Estrogens
Neoplasms
Experimental
Cell cycle
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
female genital diseases and pregnancy complications
Ovarian surface epithelium
030104 developmental biology
Oncology
Receptors
Estrogen
Estrogen
Organ Specificity
030220 oncology & carcinogenesis
Cancer research
Female
Ovarian cancer
Receptors
Progesterone
Genotoxicity
Research Article
Zdroj: BMC Cancer
BMC Cancer, Vol 20, Iss 1, Pp 1-9 (2020)
ISSN: 1471-2407
Popis: 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.
Databáze: OpenAIRE
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