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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Resveratrol represses estrogen-induced mammary carcinogenesis through NRF2-UGT1A8-estrogen metabolic axis activation
Xueyan Zhou1, Yun Zhao1, Juan Wang1
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Abstract:
Estrogen plays a pivotal role in the pathological development of breast cancer. Resveratrol has chemo-preventive effects against breast cancer, whereas, the mechanism of antitumor activities of resveratrol remains unanswered. In this study, we showed that estrogen homeostasis profile was disturbed in both breast cancer patients and in experimental breast cancer model rats, with carcinogenic catechol estrogens significantly accumulated in the mammary tissues. UDP-glucuronosyltransferase 1A8 (UGT1A8) is an important phase II drug-metabolizing enzymes which involved in the metabolism of catechol estrogens. Here we found that the mammary nuclear factor erythroid 2-related factor 2 (NRF2) - UGT1A8 signaling was down-regulated in breast cancer rats, whereas treatment with resveratrol could upregulate the expression of NRF2 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer. In addition, luciferase reporter assay suggested that resveratrol activated the expression of UGT1A8 by up-regulating the transcriptional activity of NRF2. Small-interfering RNA-mediated silencing of NRF2 abolished resveratrol-mediated preventive effects indicated that the antitumor effect of resveratrol is based on NRF2-UGT1A8-estrogen metabolism axis. Taken together, we established the resveratrol regulating potential on estrogen homeostasis based on NRF2-UGT1A8 signaling pathway, and also provided a novel link between estrogen glucuronidation metabolism and breast cancer pathological development.
Insights
Resveratrol prevents breast cancer by restoring estrogen balance. It upregulates NRF2-UGT1A8 signaling, enhancing catechol estrogen metabolism and reducing DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Estrogen is crucial in breast cancer development.
- Resveratrol exhibits chemo-preventive properties, but its mechanism is unclear.
- Estrogen homeostasis is disrupted in breast cancer, leading to carcinogenic catechol estrogen accumulation.
Purpose of the Study:
- To elucidate the mechanism behind resveratrol's antitumor activity in breast cancer.
- To investigate the role of the NRF2-UGT1A8 signaling pathway in estrogen metabolism and breast cancer.
- To establish resveratrol's potential in regulating estrogen homeostasis via this pathway.
Main Methods:
- Studied estrogen homeostasis in breast cancer patients and rat models.
- Investigated the expression of UDP-glucuronosyltransferase 1A8 (UGT1A8) and nuclear factor erythroid 2-related factor 2 (NRF2).
- Utilized resveratrol treatment, luciferase reporter assays, and small-interfering RNA (siRNA) for NRF2 silencing.
Main Results:
- Breast cancer rat models showed down-regulated mammary NRF2-UGT1A8 signaling.
- Resveratrol treatment upregulated NRF2 and UGT1A8, accelerating catechol estrogen metabolism.
- Resveratrol inhibited estrogen-induced DNA damage and suppressed breast cancer development.
- Luciferase assays confirmed resveratrol activates UGT1A8 via NRF2 transcriptional activity.
- NRF2 silencing abolished resveratrol's preventive effects, highlighting the NRF2-UGT1A8-estrogen metabolism axis.
Conclusions:
- Resveratrol's antitumor effects in breast cancer are mediated by the NRF2-UGT1A8-estrogen metabolism axis.
- Resveratrol regulates estrogen homeostasis through the NRF2-UGT1A8 signaling pathway.
- This study reveals a novel link between estrogen glucuronidation metabolism and breast cancer pathology.
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