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Molecular Mechanism of Binding between 17?-Estradiol and DNA.

ABSTRACT: Although 17?-estradiol (E2) is a natural molecule involved in the endocrine system, its widespread use in various applications has resulted in its accumulation in the environment and its classification as an endocrine-disrupting molecule. These molecules can interfere with the hormonal system, and have been linked to various adverse effects such as the proliferation of breast cancer. It has been proposed that E2 could contribute to breast cancer by the induction of DNA damage. Mass spectrometry has demonstrated that E2 can bind to DNA but the mechanism by which E2 interacts with DNA has yet to be elucidated. Using all-atom molecular dynamics simulations, we demonstrate that E2 intercalates (inserts between two successive DNA base pairs) in DNA at the location specific to estrogen receptor binding, known as the estrogen response element (ERE), and to other random sequences of DNA. Our results suggest that excess E2 has the potential to disrupt processes in the body which rely on binding to DNA, such as the binding of the estrogen receptor to the ERE and the activity of enzymes that bind DNA, and could lead to DNA damage.

SUBMITTER: Hilder TA

PROVIDER: S-EPMC5196241 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Molecular Mechanism of Binding between 17β-Estradiol and DNA.

Hilder Tamsyn A TA Hodgkiss Justin M JM

Computational and structural biotechnology journal 20161212

Although 17β-estradiol (E2) is a natural molecule involved in the endocrine system, its widespread use in various applications has resulted in its accumulation in the environment and its classification as an endocrine-disrupting molecule. These molecules can interfere with the hormonal system, and have been linked to various adverse effects such as the proliferation of breast cancer. It has been proposed that E2 could contribute to breast cancer by the induction of DNA damage. Mass spectrometry ...[more]

PMID: 28066533

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Project description:Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.

Dataset Information

Molecular Mechanism of Binding between 17?-Estradiol and DNA.

Publications

Molecular Mechanism of Binding between 17β-Estradiol and DNA.

Similar Datasets

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