PRAGYA SANTRA, AMITY UNIVERSITY KOLKATA
Loss of genomic stability prejudice genomic consistency, genetic makeup, and promote malignancies. Pathological mutations of DNA repair genes result in ovarian-cancer (OvCa). The elevation of damage burden proportionates to the elevated estrogen level, inducing DNA lesions that are dependent on the expression of hormone-receptors in G1, G2, and S phase. DNA lesions trigger signals to DNA damage responses (DDR) to prevent loss and gain of genetic information. Deleterious mutation in DDR impair genomic stability leading to point mutation and conformational aberrations, eventually promoting carcinogenesis.
High-grade OvCa depletes homologous recombination (HR) genes, BRCA1, and BRCA2 which promotes the genotoxicity of estrogen. The increment of DNA lesions corresponds to the ubiquitous activation of BRCA1. The risk of homologous recombination deficiency (HRD) is mainly limited in breast-tissues, ovary, and prostate. Steroid hormones, estrogen, progestogen, androgen, and their derivatives, are genotoxic to ovarian epithelial cells and fallopian epithelium; further obligating the functions of HR genes. Activation of hormone receptors induces double-stranded break (DSB) in endogenous DNA which is elevated in the G1 phase of breast cancer, influenced by the promoted estrogen level. It is favoured in the G1 phase for the absence of homologous sister chromatids. The genomic imprinting of BRCA1-mutated genes is distinct from BRCA2-mutated genes, focusing on varying mutational mechanisms.
At the advanced cancer-stage, the uncontrolled DNA replication in rapidly-proliferating cancer cells risks DNA damages. A high level of steroid hormones often induces ovarian surface epithelium to undergo cycles of proliferation, damage, and repair, termed as ovarian-trauma; in association to high estrogen concentration which induces strong mutagenic effects on the ovarian epithelium. Storming steroid hormones may impair the genomic integrity of non-cancerous cells located at the pro-carcinogenic sites. DDR is also observed in fallopian tubes. BRCA1 mutation and precancerous lesions are detected in fallopian tubes. Pathogenic mutations in BRCA1 and BRCA2 would exacerbate the mutagenic potential of the periodical hormonal challenge.
Concludingly the study focuses on the mechanistic clue on dis-balanced estrogen level and tissue-specific impact of HR deficiency along with BRCA1 and BRCA2 contributing to ovarian cancers. Hormonal genotoxicity to ovarian and fallopian epithelial cells is at present a trending research subheading to predetermine the cancer susceptibility in female organs and their treatments.
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SOURCE:Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium; Song, L., Tang, Z., Peng, C. et al.; 21 October 2020; BMC Cancer 20, 1020; DOI: https://doi.org/10.1186/s12885-020-07524-7
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