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

Carcinogenesis  2019 June 14 | https://doi.org/10.1093/carcin/bgz117  

Revathy Nadhan, Jayashree V Vaman, Satheesh Kumar Sengodan, Sreelatha K Hemalatha, C Nirmala, Santha Sadasivan, P V Aysha, Sreelekha Yesodharan, R S Krishnapriya, B V Amritha Krishna, Sreevidya P S, Arathi Rajan, Neetha Rajan Latha, Geetu Rose Varghese, Ratheeshkumar Thankappan, Sarada Achyutuni, Dev S U Jithin, T V Anil Kumar, Priya Srinivas

Abstract

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of ‘β-hCG’ with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates β-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- β-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 β-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 Sree Avittom Thirunal (SAT) Hospital, Thiruvananthapuram, which points out that 11.5% of gestational trophoblastic neoplasia (GTN) cases were referred to Regional Cancer Centre, 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.

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