BRCA1 promoter hypermethylation in human placenta: A hidden link with ß-hCG expression

Gestational Trophoblastic Diseases (GTD) is group of pregnancy related tumors characterized by abnormal levels of "ß-hCG" with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild type BRCA1 transcriptionally regulates ß-hCG in Triple Negative Breast Cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- ß-hCG relationship and unraveling etio-pathology of GTD. BRCA1 level in GTD is down-regulated due to the over-expression of DNMT3b and subsequent promoter hypermethylation, when compared to the normal placentae accompanied with its shift in localization. There is an inverse correlation of serum -hCG levels with BRCA1 mRNA expression. The effects of Methotrexate (MTX), which is the first line chemotherapeutic used for GTD treatment, when analyzed in comparison with Plumbagin (PB) revealed that PB alone is efficient than MTX alone or MTX-PB in combination, in showing selective cytotoxicity against GTD. Interestingly, PB increases BRCA1 levels post treatment, altering DNMT3b levels and resultant BRCA1 promoter methylation. Also, cohort study analyzed the incidence of GTD at SAT Hospital, Thiruvananthapuram, which points out that 11.5% of Gestational Trophoblastic Neoplasia (GTN) cases were referred to Regional Cancer Centre (RCC), Thiruvananthapuram, for examination of breast lumps. This has lend clues to supervene the risk of GTD patients towards BRCA1 associated diseases and unveil novel therapeutic for GTD, a plant derived naphthoquinone, PB, already reported as selectively cytotoxic against BRCA1 defective tumors. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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